Study of 1,3-dipolar cycloaddition of amino-acid azomethines and Juglone

Article abstract of DOI:10.1080/00397911.2020.1795880

Novel 2,3,4,9-tetrahydro- and 4,9-dihydro-1H-benzo[f]isoindole derivatives were synthesized from Juglone and amino-acid azomethines in 74–85% yields via 1,3-dipolar cycloaddition. The stereo- and regioselectivity of cycloaddition was confirmed by NMR spec

Full text of DOI:10.1080/00397911.2020.1795880

Synthetic Communications
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Study of 1,3-dipolar cycloaddition of amino-acid
azomethines and Juglone
Vadym Syngaevsky , Andrew Karkhut , Sviatoslav Polovkovych , Andrzej
Gzella , Roman Lesyk & Volodymyr Novikov
To cite this article: Vadym Syngaevsky , Andrew Karkhut , Sviatoslav Polovkovych , Andrzej
Gzella , Roman Lesyk & Volodymyr Novikov (2020): Study of 1,3-dipolar cycloaddition of amino-
acid azomethines and Juglone, Synthetic Communications, DOI: 10.1080/00397911.2020.1795880
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https://doi.org/10.1080/00397911.2020.1795880
Study of 1,3-dipolar cycloaddition of amino-acid
azomethines and Juglone
a
a
a
Vadym Syngaevsky , Andrew Karkhut
, Sviatoslav Polovkovych
, Andrzej
b
c,d
a
Gzella , Roman Lesyk
, and Volodymyr Novikov
a
Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology, Lviv
b
Polytechnic National University, Lviv, Ukraine; Department of Organic Chemistry, Poznan University of
Medical Sciences, Poznan, Poland; Department of Pharmaceutical, Organic and Bioorganic Chemistry,
Danylo Halytsky Lviv National Medical University, Lviv, Ukraine; Department of Public Health, Dietetics
c
d
and Lifestyle Disorders, Faculty of Medicine, University of Information Technology and Management in
Rzeszow, Rzeszow, Poland
ABSTRACT
ARTICLE HISTORY
Novel 2,3,4,9-tetrahydro- and 4,9-dihydro-1H-benzo[f]isoindole deriva-
tives were synthesized from Juglone and amino-acid azomethines in
Received 9 May 2020
7
4–85% yields via 1,3-dipolar cycloaddition. The stereo- and regiose-
KEYWORDS
lectivity of cycloaddition was confirmed by NMR spectra and single-
crystal X-ray diffraction analysis.
1
3-cycloaddition; amino
acids; azomethines; Juglone;
X-ray
GRAPHICAL ABSTRACT
1
MeOOC
O
R
MeOOC
O
COOMe
O
O
NH
N
H
or
1
O
O
OH
2
R
OH
Cl
OH
1
2
3
3
a. R = Me, R = H, 79%
b. R = Ph, R = Br, 85%
4
, 74%
1
2
Introduction
The cycloaddition reactions occupy a prominent place in synthetic organic chemistry.
For many years, the reaction of 1,3-dipolar cycloaddition has evolved into a generally
applicable method for the synthesis of five-membered heterocyclic rings, since many
[
1–11]
1
,3-dipoles are readily available and react with a wide variety of dipolarophils.
Moreover, this approach enables to generate rings containing several adjacent stereocen-
ters in one synthetic operation. The configurations of these new stereocenters are due
to the geometry of the dipole and dipolarophile as well as the mechanism of cycloadd-
ition. In recent years, numerous natural and synthetic products have been prepared by
[
12–14]
synthetic routes via 1,3-dipolar cycloadditions.
CONTACT Roman Lesyk
dr_r_lesyk@org.lviv.net
Department of Pharmaceutical, Organic and Bioorganic
Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
V. SYNGAYEVSKY ET AL.
1
MeOOC
O
R
NH
H
1
O
R
COOMe
O
2
N
R
OH
+
1
2
3
3
a. R = Me, R = H, 79%
b. R = Ph, R = Br, 85%
i
1
2
1
OH
O
MeOOC
COOMe
O
N
2
R
1
2
2
2
2
a. R = Me, R = H
1
2
b. R = Ph, R = Br
1
2
c. R = CH COOMe, R = Cl
O
OH 4, 74%
2
Cl
Scheme 1. Reaction of Schiff’s bases of amino acids with 5-hydroxy-1,4-naphthoquinone. Reagents
and conditions: i – appropriate imine (1.0 equiv.), 5-hydroxy-1,4-naphthoquinone (2.0 equiv.), AcOAg
ꢀ
(
0.1 equiv.), TEA (0.5 equiv.), PPh (0.1 equiv.), toluene, 12–24 h 60 C/24 h rt.
3
The cycloaddition of azomethine ylides as 1,3-dipoles with alkenes is a useful tool for
the construction of the pyrroline or pyrrolidine ring contained in many biologically
[
15,16]
active compounds.
Pharmacologically important pyrrole derivatives possesses anti-
[
17–19]
[17]
[17,20]
[21–23]
bacterial,
antifungal,
antiviral
anti-inflammatory,
hypolipidemic,
anti-
[
24–26]
[27–31]
cancer,
activity, etc. Pyrrole and pyrrolidine systems are used as
[
32,33]
effective intermediates in the synthesis of natural alkaloids
and synthetic nitrogen-
In addition, the issue of diastereo- and enantioselectivity of
such processes remain key for further research, especially for the design of potential
[
34]
containing heterocycles.
[
10,34–41]
biologically active compounds.
The high activity of 1,4-naphthoquinones (as the
synthetic analogs of electron-deficient alkenes) is explained by the strong electrophilic
nature of the C¼C bond due to the electron-withdrawing effects of the adjacent car-
[
10,11,39,41]
bonyl groups.
Its global electrophilicity x ¼ 3.34 eV makes it an active dipolar-
ophile in the reaction of [3 þ 2]-cycloaddition.
Results and discussion
This paper covers the reactions of azomethines (Schiff’s bases) of amino acids (2a–c) with
the cyclic dipolarophile 5-hydroxy-1,4-naphthoquinone (Juglone). Azomethines 2a–c were
obtained with 82–90% yields and sufficient purity via reaction of amino acid methyl esters
and aromatic aldehydes in dichloromethane in the presence of magnesium sulfate accord-
[
42]
ing to the known method. Heating the imines (2a–c) with Juglone in toluene for varying
periods of time gave high yields of substituted pyrrolines 3a,b and 4 (Scheme 1).
1
According to the H NMR spectra and X-ray data (ESI) mentioned cycloadditions
were regio- and diastereoselective. Juglone has a strong hydrogen bond between
the adjacent hydroxyl and carbonyl groups. Therefore, the hydroxyl substituent acts as
electron acceptor and the LUMO is highly polarized with the larger coefficient at the
[
43]
C2-position.
It explains the regioselectivity of the process. In turn, the diastereoselec-
[
35,36,44–47]
tivity of this reaction may be due to the use of silver acetate as a catalyst.

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Figure 1. Chelating silver complex of azomethine ylides.
Scheme 2. Plausible mechanism of 1,3-dipolar cycloaddition of amino-acid azomethines and Juglone.
Figure 2. ORTEP view of 3a showing the atomic labeling scheme. Non-H atoms are drawn as 30%
probability displacement ellipsoids and H atoms are drawn as spheres of an arbitrary radius.
Thus, it is known that the use of monovalent metal salts as catalysts leads to the forma-
[
35]
tion of exclusively cis-adducts.
This is possible due to the stereocoordination of the
reactive ylide in the transition state. The reaction between the chelating complexes of
azomethine ylides (Figure 1) begins with the approximation of the most electrophilic
and nucleophilic sites of the reacting molecules, namely, the C2 atom of the activated
C¼C bond of Juglone and the a-Carbon atom of azomethine ylide, which is consistent
with the possible canonical forms of azomethine ylides (Scheme 2). Mechanistically, the
dehydrogenation to compounds 3a,b and 4 could be proposed via tautomeric aroma-
tization or enolization of intermediates followed by the oxidation by the excess of
[
47–52]
Juglone or by air.

4
V. SYNGAYEVSKY ET AL.
Figure 3. ORTEP view of two symmetry-independent molecules of 3b, showing the atomic labeling
scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are depicted as
small spheres of an arbitrary radius.
Figure 4. ORTEP view of 4. Non-H atoms are drawn as 30% probability displacement ellipsoids, and
H atoms are drawn as spheres of an arbitrary radius. The disordered part of the molecule is colored
gray. Two enantiomers are presented separately.

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Structural features of 3a,b and 4 were confirmed by X-ray diffraction study (ESI).
The ORTEP drawing of 3a,b structures and atomic numberings are shown in Figures 2
and 3. Compound 3a crystallizes in the space group P-1 (DMF) with one molecule in
the asymmetric unit while compound 3 b crystallizes in the space group P21/c (AcOMe)
with two symmetry independent molecules in the asymmetric unit, denoted A and B
(Figure 3), which differ to a rather moderate extent in conformation. The differences
concern primarily the angular arrangement of the substituents present in the C1 and C3
positions of the 4,9-dioxo-2,3,4,9-tetrahydro-1H-benzo[f]isoindole system.
The spatial geometry of the molecule of 4 is presented in Figure 4. Structural investi-
gations have shown that in the crystal, most atoms of the molecule occupy two alterna-
tive positions marked a and b. The positions of atoms are related to two alternative
enantiomeric forms, in which the methoxycarbonyl and methoxycarbonylmethyl groups
are located at C1 stereogenic center on the opposite sites (Figure 4).
Conclusions
In summary, we have successfully developed an efficient regio- and diastereoselective
method for the construction of 1H-benzo[f]isoindole derivatives via 1,3-dipolar cyclo-
addition of amino-acid azomethines and Juglone.
Experimental
All the chemicals were purchased from Aldrich Chemical Company (USA) and were
used without further purification. Melting points (m.p.) were determined using an SRS-
EZMelt automated melting point instrument without correction. The elemental analyses
1
13
were performed using the Perkin–Elmer 2400 CHN analyzer. The H and C NMR
1
13
spectra were recorded on AVANCE (Bruker) spectrometer ( H at 400 and C at
00 MHz) instrument in CDCl . Chemical shifts (d) are given in ppm units relative to
1
3
tetramethylsilane as reference (0.00). HRMS spectra were obtained on an MicrOTOF-Q
III (Bruker) spectrometer. The purity of all obtained compounds was checked by TLC
on Silufol-254 plates (eluent hexane/EtOAc 1:1).
General procedure of 1,3-cycloaddition affording 3a,b and 4
AcOAg (0.032 mg, 0.19mmol) and PPh (0.049 mg, 0.19mmol) were dissolved in toluene
3
(2 mL) and stirred at room temperature for about 1 h Under argon atmosphere. Then, imine
substrate (1.93mmol), and Juglone (3.86mmol) were added sequentially, after that the mix-
ꢀ
ture was cooled to 0 C and TEA (0.091 mg, 0.095 mmol) was added. Then it was heated to
ꢀ
6
0 C and maintained for 24h. Once starting material was consumed (monitored by TLC),
the resulting mixture was evaporated in a vacuum. The mixture was purified by chromatog-
raphy on SiO hexanes/EtOAc gradient elution from 1:99 to 50:50 to give target product.
2
rel-(1R,3R)-5-Hydroxy-1-methyl-4,9-dioxo-3-phenyl-2,3,4,9-tetrahydro-1H-benzo[f]isoin-
dole-1-carboxylic acid methyl ester (3a). Yield 79%, red-brown plate crystal, mp 143-
ꢀ
1
1
7
45 C. H NMR (400 MHz, CDCl ) d, ppm: 11.71 (s, 1H, OH); 7.64 (dd, 1H, J ¼
3
1
.6 Hz, J ¼ 1.5 Hz, CH); 7.60 (t, 1H, J ¼ 7.9 ꢁ 2 Hz, CH); 7.44–7.40 (m, 2H, 2CH);
2

6
V. SYNGAYEVSKY ET AL.
7
.38-7.27 (m, 4H, 3CH, 1NH); 7.22 (dd, 1H, J ¼ 8.2 Hz, J ¼ 1.5 Hz, CH); 5.66 (s, 1H,
1
2
1
3
CH); 3.78 (s, 3H, OCH ), 1.78 (s, 3H, CH ). C NMR (100 MHz, CDCl ) d: 24.6, 52.9,
3
3
3
6
1
6.5, 71.2, 115.9, 119.4, 124.9, 127.7, 128.3, 128.8, 133.2, 136.5, 141.1, 148.9, 149.9,
þ
61.8, 172.9, 181.1, 187.6. HRMS (ESI): calcd. for C H NO [M þ H] 364.1179;
21
18
5
found: 364.1175. Anal. calcd for C H NO : C, 69.41, H, 4.72, N, 3.85. Found: C,
2
1
17
5
69,50; H, 4.80; N, 3.70.
X-ray diffraction studies
Crystallographic data for 3a
Empirical formula: C H NO , formula weight 363.36, triclinic, space group P-1,
2
1
17
5
a ¼ 7.3424(4), b ¼ 8.1185(3), c ¼ 14.4387(6) Å, a ¼ 101.308(3), b ¼ 93.859(4),
ꢀ
3
3
ꢂ1
c ¼ 94.273(4) , V ¼ 838.67(6) Å , Z ¼ 2, D
¼ 1.439 g/cm , m ¼ 0.857 mm ,
calc
T ¼ 130.0(1) K. A red-brown plate crystal (DMF) of 0.25 ꢁ 0.20 ꢁ 0.05 mm was used to
ꢀ
record 16180 (Cu Ka-radiation, h
¼ 75.96 ) intensities on a Rigaku SuperNova Dual
max
Atlas diffractometer using mirror monochromatized Cu Ka radiation from a high-flux
microfocus source (k ¼ 1.54178 Å). The supplementary crystallographic data of 3a have
been deposited at the Cambridge Crystallographic Data Center (CCDC) as a supple-
mentary publication CCDC 1900363. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union ROAD, Cambridge CB2 1EZ (UK) (fax: þ44-
(
0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Crystallographic data for 3b
Empirical formula: C H BrNO , formula weight 504.32, monoclinic, space group P2 /
2
6
18
5
1
ꢀ
c,
a ¼ 19.35586(17),
b ¼ 16.30452(16),
c ¼ 13.34255(10)
Å,
b ¼ 91.0173(7) ,
3
3
ꢂ1
V ¼ 4210.08(6) Å , Z ¼ 8, D
¼ 1.591 g/cm , m ¼ 3.010 mm , T ¼130.0(1) K. A red
calc
lath crystal (AcOEt) of 0.22 ꢁ 0.14 ꢁ 0.05 mm was used to record 44382 (Cu Ka-radi-
ꢀ
ation, h
¼ 76.55 ) intensities on a Rigaku SuperNova Dual Atlas diffractometer using
max
mirror monochromatized Cu Ka radiation from a high-flux microfocus source
(
k ¼ 1.54178 Å). The supplementary crystallographic data of 3b have been deposited at
the Cambridge Crystallographic Data Center (CCDC) as a supplementary publication
CCDC 1900364. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union ROAD, Cambridge CB2 1EZ (UK) (fax: þ44-(0)1223-336033 or e-
mail: deposit@ccdc.cam.ac.uk).
Crystallographic data for 4. Empirical formula: C H ClNO , formula weight 453.82,
23
16
7
triclinic, space group P-1, a ¼ 7.8945(3), b ¼ 10.6545(4), c ¼ 13.0942(5) Å, a ¼ 70.282(4),
ꢀ
3
3
b ¼ 81.576(3), c ¼ 74.872(4) , V ¼ 998.80(7) Å , Z ¼ 2, D
¼ 1.509 g/cm , m ¼
calc
ꢂ1
2
.126 mm , T ¼130.0(1) K. A red lath crystal (AcOEt) of 0.20 ꢁ 0.15 ꢁ 0.05 mm was
ꢀ
used to record 18505 (Cu Ka-radiation, h
¼ 76.38 ) intensities on a Rigaku
max
SuperNova Dual Atlas diffractometer using mirror monochromatized Cu Ka radiation
from a high-flux microfocus source (k ¼ 1.54178 Å). The supplementary crystallographic
data of 4 have been deposited at the Cambridge Crystallographic Data Center (CCDC)
as a supplementary publication CCDC 1900365. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union ROAD, Cambridge CB2 1EZ (UK)
(fax: þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

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Supplementary information
Supplementary data (spectral and analytical data for compounds 3a,b and 4) associated with this
article can be found, in the online version, at http://dx.doi.org/10.1080/00397911.2020.1795880.
Acknowledgments
We would like to express the warmest appreciation to Erasmus þ program aims to support
actions in the fields of Education, Training, Youth and Sport for the period 2014–2020 and to
Professor Arnaud Martel (Le Mans University, France) for support and assistance in conduct-
ing research.
ORCID
Andrew Karkhut
Sviatoslav Polovkovych
Roman Lesyk
http://orcid.org/0000-0003-2386-1973
http://orcid.org/0000-0002-7143-6931
http://orcid.org/0000-0002-3322-0080
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