Highly efficient and stereoselective cycloaddition of nitrones to indolyl- and pyrrolylacrylates

Article abstract of DOI:10.1016/j.tetlet.2018.04.066

The reactions of various nitrones with indolyl- and pyrrolylacrylates proceeds regioselectively with high diastereoselectivity in the case of aldonitrones, and represents an effective method for obtaining new indolyl- and pyrrolyl-substituted isoxazolidin

Full text of DOI:10.1016/j.tetlet.2018.04.066

Accepted Manuscript
Highly efficient and stereoselective cycloaddition of nitrones to indolyl- and
pyrrolylacrylates
Viktor A. Dmitriev, Mariia M. Efremova, Alexander S. Novikov, Vladimir V.
Zarubaev, Alexander V. Slita, Anastasia V. Galochkina, Galina L. Starova,
Andrey V. Ivanov, Alexander P. Molchanov
PII:
S0040-4039(18)30539-2
https://doi.org/10.1016/j.tetlet.2018.04.066
TETL 49929
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
3 March 2018
16 April 2018
24 April 2018
Please cite this article as: Dmitriev, V.A., Efremova, M.M., Novikov, A.S., Zarubaev, V.V., Slita, A.V., Galochkina,
A.V., Starova, G.L., Ivanov, A.V., Molchanov, A.P., Highly efficient and stereoselective cycloaddition of nitrones
to indolyl- and pyrrolylacrylates, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.066
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Highly efficient and stereoselective
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pyrrolylacrylates
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Victor A. Dmitrieva, Mariia M. Efremovaa, *, Alexander S. Novikova,Vladimir V. Zarubaevb, Alexander V.
Slitab, Anastasia V. Galochkinab, Galina L. Starovaa, Andrey V. Ivanovc and Alexander P. Molchanova, 
a Saint Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation
b Pasteur Institute of Epidemiology and Microbiology, 14 Mira str., 197101 St. Petersburg, Russia
cA.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str.,
Irkutsk 664033, Russian Federation

1
Tetrahedron Letters
Highly efficient and stereoselective cycloaddition of nitrones to indolyl- and
pyrrolylacrylates
Viktor A. Dmitrieva, Mariia M. Efremovaa, Alexander S. Novikova, Vladimir V. Zarubaevb, Alexander V.
Slitab, Anastasia V. Galochkinab, Galina L. Starovaa, Andrey V. Ivanovc and Alexander P. Molchanova, 
a
Saint Petersburg State University, Universitetskaya nab. 7/9, St. Petersburg 199034, Russian Federation
Pasteur Institute of Epidemiology and Microbiology, 14 Mira str., 197101 St. Petersburg, Russia
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., Irkutsk 664033, Russian Federation
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reactions of various nitrones with indolyl- and pyrrolylacrylates proceeds regioselectively
with high diastereoselectivity in the case of aldonitrones, and represents an effective method for
obtaining new indolyl- and pyrrolyl-substituted isoxazolidine carboxylates stabilized by weak
(С–H···O) and moderate (N–H···N) strength intramolecular hydrogen bonding. The resulting
cycloadducts exhibit promising in vitro anti-influenza activities.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
indoles
cycloaddition
nitrones
isoxazolidines
1. Introduction
vinylpyrroles and indoles with 1,3-dipoles (nitrones, nitrile
oxides, azomethine imines). It has been shown that in the absence
The isoxazolidine ring is an important structural fragment of
natural compounds and biologically active substances.1
Isoxazolidine derivatives exhibit
of a catalyst, the reaction proceeds to give the corresponding
(3+2)-cycloadducts in good yields via reaction of the vinyl
double bond.9 However, in the case of nitrones and azomethine
imines in the presence of Lewis acids, a change of reaction path
was observed and polycyclic products of formal (3+3)-
cycloaddition were obtained instead of adducts of 1,3-dipolar
cycloaddition.10 It should be noted that these reactions are not
only an effective method for the construction of heterocyclic
systems including the pyrrole ring, but they are also of interest
for theoretical investigations of the details of the 1,3-dipolar
cycloaddition mechanism.11 Previously, we investigated only N-
vinylpyrroles and indoles without any substituents on the vinyl
double bond9 or N-propadienyl heterocycles.12 The only known
example of the reaction of indolylacrylate with 1,3-dipoles is a
catalytic reaction with an azomethine imine.13 It is known that
both steric and electronic factors are important to the regio-
selectivity of the 1,3-dipolar cycloaddition of unsymmetrical
dipolarophiles. Aldonitrones add to variously substituted
acrylates to give 4- or 5-isoxazolidinecarboxylates14. Also, the
presence of an ethoxycarbonyl group raises the diversity of the
synthesized products.
a
wide range of
pharmacological properties, in particular antiviral,2 antibacterial3
and antitumor4 activities. It should be noted that the formation of
intramolecular hydrogen bonds has a pronounced effect on the
binding ability of these compounds with enzymes or receptors
and also their membrane permeability, water solubility, and
lipophilicity.5 Isoxazolidines are valuable intermediates because
the N-O bond can be easily cleaved under mild reducing
conditions to afford 1,3-aminoalcohols, which themselves are
highly valuable synthetic building blocks in the synthesis of
analogues of natural compounds: e.g. alkaloids and β-lactam
antibiotics.6a One of the most convenient and widely studied
methods for the synthesis of substituted isoxazolidines is the 1,3-
dipolar cycloaddition of nitrones to the C=C double bond.6 The
undoubted advantage of this method is the possibility of
selectively obtaining a molecule containing several stereocenters.
In addition, indole and pyrrole derivatives can react with
dipoles giving a wide range of products depending on the
structures of the reagents and the reaction conditions. Indole and
pyrrole fragments, due to their high nucleophilicity, directly react
with 1,3-dipoles giving products of alkylation7 or cycloaddition8
as well as activating conjugated multiple bonds for 1,3-dipolar
The aim of this work is the detailed experimental study of the
reactions of indolyl- and pyrrolylacrylates with nitrones as a
highly efficient way to synthesise indolyl- and pyrrolyl-
substituted isoxazolidinecarboxylates. The study is supported by
c—yc—loa—ddition. Recently, we investigated the reactions of N-
 Corresponding author. e-mail: a.molchanov@spbu.ru

2
Tetrahedron
theoretical investigations of the nature and energies of
Inspection of the crystallographic data suggests the presence
of intramolecular hydrogen bonding (N–H···N and С–H···O)
which is responsible for the conformation of 5a in the solid state,
viz. N(25)–H···N(2), С(17)–H···O(13), and С(31)–H···O(13).
Indeed, the observed distances H···N (2.187 Å) and H···O (2.304
and 2.621 Å) are shorter than the sum of Bondi’s16 vdW radii for
the appropriate atoms (2.75 and 2.72 Å, respectively). Taking
into account the significance of such weak contacts,5 additional
structural analysis through a computational study was desirable.
intramolecular hydrogen bonding (N–H···N and С–H···O) which
is responsible for the conformation of the resulting compounds
and the testing of their antiviral activity.
2. Results and Discussion
Our study began with an investigation of the reactions of
indolyl- and pyrrolylacrylates 1-3 with highly reactive C-
carbamoylnitrones 4a-d. The reactions were carried out at 110 °C
Table 1. Reactions of acrylates 1-3 with nitrones 4a-d.
R3
R2
R3
R4
O
R2
R1
N
O
Toluene,
110 oC
N
CO2Et
H
N
R1
+
N
H
N
N
O
R5
CO2Et
R4
O
4a-d
1-3
R5
5a-i
No Acrylate Nitrone
R1
R2
R3
R4
R5
Product
Time (h)
Isolated yield (%)
1
2
4
3
5
6
7
8
9
1
1
1
1
2
2
2
3
3
4a
4b
4c
4d
4a
4b
4c
4a
4b
-(CH)4-
-(CH)4-
-(CH)4-
-(CH)4-
-(CH)4-
-(CH)4-
-(CH)4-
H
H
Ph
p-Tol
p-Tol
Me
H
H
5a
5b
5c
5d
5e
5f
30
20
60
100
30
30
60
30
30
98
92
76
62
86
67
78
60
75
H
OMe
H
H
Me
Me
Me
H
Ph
H
p-Tol
p-Tol
Ph
H
OMe
H
5g
5h
5i
p-Cl-C6H4
p-Cl-C6H4
H
H
H
p-Tol
H
in toluene for 20-100 hours. The reactions proceeded regio- and
diastereoselectively resulting in good to excellent yields of 5-
indolyl- or pyrrolyl-substituted isoxazolidinecarboxylates as
In order to confirm or deny the existence of these weak contacts
and quantify their energies from a theoretical point of view, we
carried out DFT calculations and performed a topological
analysis of the electron density distribution within the framework
of Bader's theory (QTAIM method)17 for model structure 5a (see
ESI for details; this methodology has already been successfully
used by us previously).18
1
single diastereomers in all cases (Table 1). The H NMR spectra
of the crude reaction mixtures did not contain signals of any
other regio- or diastereoisomers. The structure of all adducts
were established on the basis of spectroscopic data, and the
relative configuration of adduct 5a was confirmed using single
crystal X-ray diffraction analysis (Fig. 1).15
The QTAIM analysis demonstrates the presence of
appropriate bond critical points (BCP’s) (3, –1) for
intramolecular hydrogen bonding N–H···N and С–H···O in the
optimized equilibrium structure of 5a (Table S1, Fig. S1, ESI).
The energies for these contacts were defined according to the
procedures proposed by Espinosa and co-workers19 and Vener
and co-workers20 (Table S1, ESI), and one can state that these
non-covalent interactions can be classified as weak (С–H···O,
2.2–4.1 kcal/mol) and moderate (N–H···N, 5.6–5.7 kcal/mol)
strength hydrogen bonding mainly due to electrostatics following
the classification of Jeffrey21 (“weak”: <4 kcal/mol, “moderate”:
15–4 kcal/mol, “strong”: 40–15 kcal/mol).
Next, we investigated the reaction of acrylate 1 with other
aldonitrones – C,N-diarylnitrones 6a-c. These nitrones were less
reactive towards indolylacrylate 1 (Table 2). The reaction
required prolonged heating and gave only moderate yields of the
5-indolyl-substituted isoxazolidine carboxylates. In the case of
nitrone 6a, 3% of the minor diastereomer 7a' was isolated from
the reaction mixture as well as the main product 7a. The relative
configuration of adducts 7a and 7a' were additionally confirmed
Figure 1. X-ray crystal structure of 5a.

3
Table 2. Reactions of acrylate 1 with nitrones 6a-c.
Entry
Nitrone
6a
R
H
Products
7a, 7a'
7b
Time (h)
100
Isolated yield (%)
1
2
3
30 (7a), 3 (7a')
6b
Cl
100
50
25
6c
OMe
7c
80
using their 1Н–1Н NOESY spectra in which a cross-peak for the
protons in the C3- and C5-positions of the isoxazolidine ring in
structure 7a was observed.
Cleavage of the N–O bond of isoxazolidines using a variety of
reducing agents is a powerful tool in organic synthesis.
Depending on the structure of the isoxazolidine these methods
allow a wide range of both cyclic and open-chain products to be
obtained.9a, 23 To investigate the synthetic utility of the obtained
adducts, two of them were subjected to treatment with Zn/AcOH.
Cycloadduct 5b underwent isoxazolidine ring opening giving
aminoalcohol 10 (Scheme 1).
An alteration of the reaction path in the presence of Lewis
acids had been shown in our previous work for the reaction of
C,N-diarylnitrones and N-vinylpyrroles.10 An attempt was made
to use nickel(II) perchlorate in the reaction of pyrrolylacrylate 3
with nitrone 6c. However, in this case, only decomposition of the
starting nitrone occurred and the formation of any type of
cycloadducts was not observed.
Table 3. Reactions of acrylate 1 with nitrones 8a-c.
Entry
Nitrone
8a
R
H
Product
9a
Time (h)
Isolated yield (%)
1
2
3
40
40
40
68
82
77
8b
Cl
Me
9b
8c
9c
It is known that the selectivity of cycloaddition with
ketonitrones may differ from aldonitrones due to increased steric
22
hindrance.12, We investigated the cycloaddition of acrylate 1
with N-aryl-C,C-bis(methoxycarbonyl)nitrones 8a-c. The
reaction proceeded well, giving good yields of 5-indolyl-
substituted isoxazolidinecarboxylates 9a-c.
Thereby, it has been established that the cycloaddition
reactions of indolyl- and pyrrolylacrylates with different types of
nitrones proceeds regioselectively giving 5-indolyl- or pyrrolyl-
substituted isoxazolidinecarboxylates. To achieve complete
conversion of the starting nitrone, much longer heating was
required than for reactions with N-vinylindoles and pyrroles. In
Scheme 1. Reduction of isoxazolidine 5b.
The structure of aminoalcohol 10 was confirmed using single
crystal X-ray diffraction analysis (Fig. 2).24
the
case
of
aldonitrones,
the
reaction
proceeds
stereoselectively.9a-c Moreover, when using nitrones containing
electron-withdrawing substituents at the carbon atom, the
reaction proceeds faster, giving higher yields of cycloadducts.
Under the action of Zn/AcOH at room temperature, product
9b containing two ester groups at the C3-atom of the
isoxazolidine ring underwent isoxazolidine ring opening to form
diastereomeric lactones 11 and 11' (Scheme 2).

4
Tetrahedron
antivirals, amantadine and rimantadine. These compounds block
viral replication by inhibiting the activity of virus-specific proton
channel M2 thus preventing dissociation of a viral genome within
the cytoplasm. The reference drug rimantadine was inactive
against this virus (Table 4) while compound 5a demonstrated
high anti-viral potential. This suggests that it utilizes a target
other than M2 and therefore may represent a novel class of anti-
viral compounds with alternative target(s) and mode of action.
3. Conclusion
The reaction of indolyl- and pyrrolylacrylates with various
nitrones proceeds regio- and stereoselectively via 1,3-dipolar
cycloaddition, and represents an efficient way to synthesise 5-
indolyl- or pyrrolyl-substituted isoxazolidinecarboxylates
exhibiting promising in vitro anti-influenza activity. The
resulting cycloadducts are stabilized by weak (С–H···O) and
moderate (N–H···N) strength intramolecular hydrogen bonding
and can be reduced using Zn/AcOH to give 1,3-aminoalcohols or
lactones containing amino- and carboxyl functionality.
Figure
2. X-ray crystal structure of 10.
Acknowledgments
We gratefully acknowledge the financial support from the
Russian Foundation for Basic Research (projects No 16-33-
00614 and 16-33-60063). NMR, HRMS and XRD studies were
performed at the Saint Petersburg State University Center for
Magnetic Resonance, Center for Chemical analysis and materials
research and X-Ray Diffraction Center, respectively.
Scheme 2. Reduction of isoxazolidine 9b.
The relative configurations of lactones 11 and 11' were
determined by 1Н–1Н NOESY spectra. The spectrum of
compound 11' contains a cross-peak for the proton of the amino
group and the proton at the C5-atom of the lactone (see ESI).
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5
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24. Suitable crystals were obtained from ethanol. Crystallographic data for
compound 10 have been deposited at the Cambridge Crystallographic

6
Tetrahedron




Aldo- and ketonitrones add to indolyl- and
pyrrolylacrylates with high regioselectivity
In case of aldonitrones the addition
proceeds with high diastereoselectivity
1,3-cycloaddition is an efficient method
synthesise isoxazolidinecarboxylates
Isoxazolidinecarboxylates reduce by
Zn/AcOH to 1,3-aminoalcohols or lactones