First example of the cascade acylation/IMDAV/ene reaction sequence, leading to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity

Article abstract of DOI:10.1016/j.tetlet.2018.02.015

The reaction between readily accessible N-aryl-3-phenylallylamines and maleic anhydride led to unexpected products – polysubstituted hydrogenated benzo[f]isoindole-4-carboxylic acids. This transformation proceeds through a previously unknown sequence of s

Full text of DOI:10.1016/j.tetlet.2018.02.015

Accepted Manuscript
First example of the cascade acylation/ IMDAV/ ene reaction sequence, leading
to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity.
Alexander A. Voronov, Kseniia A. Alekseeva, Elena A. Ryzhkova, Vladimir V.
Zarubaev, Anastasia V. Galochkina, Vladimir P. Zaytsev, Mahesh S. Majik,
Santosh G. Tilve, Atash V. Gurbanov, Fedor I. Zubkov
PII:
S0040-4039(18)30182-5
https://doi.org/10.1016/j.tetlet.2018.02.015
TETL 49700
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 December 2017
31 January 2018
6 February 2018
Please cite this article as: Voronov, A.A., Alekseeva, K.A., Ryzhkova, E.A., Zarubaev, V.V., Galochkina, A.V.,
Zaytsev, V.P., Majik, M.S., Tilve, S.G., Gurbanov, A.V., Zubkov, F.I., First example of the cascade acylation/
IMDAV/ ene reaction sequence, leading to N-arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral
activity., Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.015
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First example of the cascade acylation/
IMDAV/ ene reaction sequence, leading to N-
arylbenzo[f]isoindole-4-carboxylic acids
possessing anti-viral activity.
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Alexander A. Voronov, Kseniia A. Alekseeva, Elena A. Ryzhkova, Vladimir V. Zarubaev, Anastasia V.
Galochkina, Vladimir P. Zaytsev, Mahesh S. Majik, Santosh G. Tilve, Atash V. Gurbanov, Fedor I. Zubkov

1
Tetrahedron Letters
First example of the cascade acylation/ IMDAV/ ene reaction sequence, leading to N-
arylbenzo[f]isoindole-4-carboxylic acids possessing anti-viral activity.
Alexander A. Voronov,a Kseniia A. Alekseeva,a Elena A. Ryzhkova,a Vladimir V. Zarubaev,b Anastasia V.
Galochkina,c Vladimir P. Zaytsev,a Mahesh S. Majik,d Santosh G. Tilve,d Atash V. Gurbanov,e,f Fedor I.
Zubkov*,a
aDepartment of Organic Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, 117198, Russian
Federation, e-mail: fzubkov@sci.pfu.edu.ru, tel.: +7 495 955 0779.
bPasteur Institute of Epidemiology and Microbiology, 14 Mira St., 197101 St. Petersburg, Russian Federation
cDepartment of Pre-clinical trials, Influenza Research Institute, 15/17 Prof. Popova St., 197376 St. Petersburg, Russian Federation
dDepartment of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
eDepartment of Organic Chemistry, Baku State University, Z. Khalilov str. 23 AZ 1148, Baku, Azerbaijan
fCentro de QuímicaEstrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. RoviscoPais, 1049-001 Lisbon, Portugal
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The reaction between readily accessible N-aryl-3-phenylallylamines and maleic anhydride led
to unexpected products – polysubstituted hydrogenated benzo[f]isoindole-4-carboxylic acids.
This transformation proceeds through a previously unknown sequence of steps: N-acylation of
the allylamine with maleic anhydride, intramolecular Diels-Alder reaction of the vinylarene in
the intermediate N-maleamide, and Alder-ene reaction of the products of the previous two
steps. Selected benzo[f]isoindoles displayed antiviral activity.
Available online
Keywords:
IMDAV reaction;
Alder-ene reaction;
benzo[f]isoindoles;
anti-viral activity;
[4+2] cycloaddition
2018 Elsevier Ltd. All rights reserved.
The intramolecular Diels-Alder reaction of vinylarenes
(IMDAV reaction) and dienes,1 particularly styrenes, represents a
useful transformation for the synthesis of annulated carbo- and
heterocycles. Despite the fact that the transition state of the
cycloaddition includes dearomatization of the benzene ring and
requires relatively harsh conditions, this methodology is widely
adopted in organic synthesis due to the ready availability of the
styrene starting materials, and the simplicity of the experimental
procedure. More interesting features of the IMDAV reaction are
usually exhibited if the reaction is involved in a cascade of
consecutive transformations. For example, the tandem IMDAV /
Alder-ene reaction2,3 proceeding through nonaromatic
intermediates can serve as a pathway towards polyfunctional
condensed arenes. The presence of an external enophile is
necessary in all known reactions of this type.3
Closely related reactions to the novel transformation reported
herein are depicted in Scheme 1. The first successful IMDAV /
Alder-ene reaction sequence was demonstrated in 1975 by the
intramolecular cyclization of amide 1.4a The possibility for the
involvement of a styrene fragment in the thermal intramolecular
Diels-Alder reaction was demonstrated using the example of
benzoisoindole (2) which was isolated in moderate yield. Should
the reaction be carried out without an inert atmosphere, the “ene-
reaction” between oxygen and the nonaromatic intermediate
1,3,3a,4,4a,9a-hexahydrobenzo[f]isoindole (similar to structure
A) would have occurred to give hydroxy derivative 3. It was also
noted that a small amount of “dimeric material” of an unknown
structure (presumably, similar to 13, see below) was formed.4a
The second example describes the IMDAV reaction of
dihalogen amides 4 leading to a mixture in which three products
5-7 were detected, each formed via intermediate A.4b The third
and the most recent example, reported that the IMDAV reaction
of maleic amides 8 bearing an electron-withdrawing substituent
(R2 = NO2) on the styrene fragment, led to adducts 9 in moderate
yields.4c At the same time, it was shown that the cycloaddition
does not depend on the configuration of the dienophile part of
amides 8 (Z or E-configuration). In contrast, if the initial styrenes
8 are unsubstituted (R2 = H), a multicomponent mixture is
formed under the same reaction conditions. In our opinion, the
latter observation is surprising, given the data of the above-
mentioned work,4a in which the intramolecular cyclization of
methylenedioxy substituted styrene (1) proceeded smoothly.
We envisioned that our ongoing studies into the IMDAV
reaction using 3-furyl- and 3-thienylallylamines,5 could help
explain the ambiguity and therefore, we were encouraged to carry
out a detailed study of this reaction in order to investigate the
transformation of 3-phenylallylamines under the action of α,β-
unsaturated carboxylic acid anhydrides.
The starting materials, 3-phenylallylamines 11a-j, were
prepared from cinnamaldehyde and ring-substituted anilines
according to a standard procedure,5 which involved condensation
and reduction steps (Scheme 2).

2
Tetrahedron
Scheme 1. Previously reported data on the IMDAV reaction of N-cinnamylamides (1, 4, 8).
Scheme 2. Synthesis of N-arylcinnamylamines 11a-j.
A subsequent solvent screen revealed that even though THF
was suitable for the reaction between 11a and maleic anhydride,
the best yields of compound 13a (Scheme 4) were obtained with
PhH and 1,4-dioxane (Entries 4 and 9, Table 1).
1,4-Dioxane turned out to be more suitable due to a shorter
reaction time and easier isolation of products, which are
precipitated after concentration of the solution by evaporation
and cooling (reactions in PhH required chromatographic
purification). Next, the optimum conditions were used for the
transformation of allylamines 11b-j into adducts 13b-j (Scheme
4, Table 2).
The reaction of N-phenylcinnamyl amine 11a, which was used
as a model compound, with the simplest and most readily
available dienophile maleic anhydride, proceeded quickly (~ 30
min at r.t) to afford maleic amide 12a in almost quantitative yield
(Scheme 3). As established by dynamic NMR experiments (ESI),
compound 12a which possesses diene and dienophile moieties
remained almost intact at temperatures below 50 °С. At higher
temperatures, the formation of compound 13a was detected in the
reaction mixture.
It is worth noting that, at the beginning of this study we
anticipated
that
the
main
products
would
be
hexahydrobenzo[f]isoindoles similar to 2, 5 and 9 (see Scheme
1). However, thorough analysis suggested that the resulting
compound 13, was composed of two molecules of the initial
amine 11 and two molecules of maleic anhydride.
Presumably, after the N-acylation of allylamines 11 under the
action of maleic anhydride, the IMDAV reaction of amides 12,
leading to the nonaromatic intermediates, benzo[f]isoindoles 14,
took place. The subsequent ene-reaction of compounds 12 and 14
proceeds with high regioselectivity, reacting only between the
more sterically accessible carbon atom of the double bond of
amide 12, next to the carboxylic group, and the C-9 carbon of the
ene-part. Like most pericyclic reactions, the Alder-ene reaction
proceeds diastereoselectively, and only one diastereoisomer of 13
was isolated from the reaction mixtures. To the best of our
knowledge, this represents the first example of a tandem IMDAV
/ Alder-ene reaction which does not require the use of an external
enophile.
Scheme 3. Intermediate amide 12a isolation.
Consequently, it could be proposed with high probability that
amides 12 are intermediates in the transformations depicted in
Scheme 4.

Scheme 4. Plausible mechanism of benzo[f]isoindole-4-carboxylic acid 13 formation.
Table 1. Optimization of the IMDAV / ene reaction conditions
Table 2. The substituents (R), yields of compounds 11, 13, and
the results of anti-viral activity tests for the H1N1 virus using
benzo[f]isoindole-4-carboxylic acids (13).
using the model reaction of cinnamyl amine 11a and maleic
anhydride.a
R1
R2
R3 Yield Yield Anti-viral activity of
Entry Solvent
Conditions
Yield 13a
(%)
44
Entry
11
(%)
13
(%)
13
IC50
1
2
PhH
PhH
80 °C, 4 h
80 °C, 8 h
a
b
CC50
876
561
294
168
726
659
31
SIc
2
6
1
2
2
3
1
2
53
a
b
c
d
e
f
g
h
H
H
Me
Me
H
MeO
CF3
H
H
Me
H
H
MeO
H
H
Ph
H
H
H
H
Me
H
H
H
H
H
H
69
80
72
61
46
43
59
67
86
62
68
41
45
31
41
53
38
52
39
68
570
100
218
73
396
209
21
340
71
17
3
4
PhH
PhH
80 °C, 15 h
80 °C, 20 h
71
77
5
6
7
8
PhH
80 °C, 36 h
80 °C, 20 h
80 °C, 20 h, ZnCl2 (10 mol%)
65 °C, 30 h
70
39
31
38
MeCN
MeCN
THF
9
10
1,4-dioxane 100 °C, 4 h
EtOH 78 °C, 2 h
68
511
79
556
b
i
j
Cl
H
1
33
6
Br
aReagents and conditions: 11a (4.0 mmol), maleic anhydride (4.0 mmol),
Rimd
OCe
N/A
N/A
1743
330
solvent (10 mL). bA multicomponent mixture was obtained.
>160 0.192 833
It was difficult to determine the precise spatial structure of the
resulting adducts 13 (especially the acyclic part) using NMR
analysis due to the occurrence of overlapping proton signals in
a50% Cytotoxic concentration (microM), concentration causing death of 50%
of cells in the culture. b50% Inhibiting concentration (microM), concentration
the low-field region of the 1H NMR spectra. Therefore, to decreasing the viral titer by 50%. cSelectivity index (SI), ratio of CC50 to IC50.
4dRimantadine is the reference compound. eOseltamivir carboxylate is the
facilitate identification of the structure, single crystal X-ray
analysis of compound 13f (R1 = MeO, R2 = R3 = H) was
reference compound.
performed to supplement the NMR analysis (Fig. 1).6
The original structure of products 13 (containing two amide
bonds and a pharmacophore isoindole fragment) motivated us to
Compound 13f comprises of the fused tricyclic system
containing
a
five-membered (pyrrolidine), six-membered
study its biological properties. The synthesized compounds 13
were tested for cytotoxicity and anti-viral activity using the MTT
test and virus yield reduction assay, respectively. In our
experiments, we used influenza virus A/Puerto Rico/8/34
(H1N1) that is widely used worldwide as a reference strain,7
particularly for screening novel potential antiviral agents. It is
worth noting that this virus is resistant to first-generation
adamantane-based anti-influenza drugs, amantadine and
rimantadine.8
(cyclohexene) and four benzene rings. The five-membered ring
has the envelope conformation; the deviation of the C-9a carbon
atom from the plane of the remaining four atoms (C-1, N, C-3,
C-3a) is ~35°. The six-membered cyclohexene ring adopts the
distorted envelope conformation with the deviation of C-3a ~56°.
The hydrogen atoms at C-3a, C-4 and C-9 in 13f are cis-oriented,
while the protons H-9 and H-9a occupy the trans-positions. The
dihedral angle between H-9 and H-9a is 168°. The planes of both
cis-oriented carboxylic groups are almost parallel. The spatial
structure of the other products 13 were assigned by analogy.

Tetrahedron
4
M.; Kocsis, L. S.; Brummond, K. M. Org. Lett. 2013, 15, 2578.
As shown in Table 2, the compounds under investigation
(g) Kocsis, L. S.; Benedetti, E.; Brummond, K. M. Org. Lett.
2012, 14, 4430. (h) Ozawa, T. Kurahashi, T.; Matsubara, S. Org.
Lett. 2011, 13, 5390.
2. For recent reviews concerning the tandem Diels-Alder / ene-
reaction, see: (a) Neier, R.; Banach, E. Curr. Org. Chem. 2016,
20, 2326. (b) Hack, D.; Blümel, M.; Chauhan, P.; Philippsa, A.
R.; Enders, D. Chem. Soc. Rev. 2015, 44, 6059. (c) Liu, X.;
Zheng, K.; Feng, X. Synthesis 2014, 46, 2241.
showed varying cytotoxicity. In general, the anti-viral activity of
the synthesized compounds was weak, with selectivity indexes
ranging from 1 to 6. Unexpectedly, compound 13j (R2 = Br, R1 =
R3 = H) showed low toxicity and the highest anti-viral activity
(SI = 33), exceeding that of another effective antiviral ribavirin
targeting the influenza virus polymerase complex.9
3. For recent papers regarding application of the tandem [4+2] /
ene reaction, see: (a) Zheng, M.; Wu, F.; Chen, K.; Zhu, S. Org.
Lett. 2016, 18, 3554. (b) Cowell, J.; Abualnaja, M.; Morton, S.;
Linder, R.; Buckingham, F.; Waddell, P. G.; Proberta, M. R.;
Hall, M. J. RSC Adv. 2015, 5, 16125. (c) Cowell, J.; Harrington,
R. W.; Probert, M. R.; Hall, M. J. Tetrahedron: Asymmetry 2015,
26, 1189. (d) Bhojgude, S. S.; Bhunia, A.; Gonnade, R. G.; Biju,
A. T. Org. Lett. 2014, 16, 676. (e) Bhojgude, S. S.; Thangaraj,
M.; Suresh, E.; Biju, A. T. Org. Lett. 2014, 16, 3576. (f)
Robinson, J. M.; Sakai, T.; Okano, K.; Kitawaki, T.; Danheiser,
R. L. J. Am. Chem. Soc. 2010, 132, 11039. (g) Lodochnikova, O.
A.; Ashirov, R. V.; Appolonova, S. A.; Litvinov, I. A.;
Plemenkov, V. V. Russ. J. Org. Chem. 2010, 46, 49.
4. For research closely related to the subject of this work, see: (a)
Cox, M. T. J. Chem. Soc., Chem. Commun. 1975, 903. (b)
Dawson, J. R.; Mellor, J. M. Tetrahedron Lett. 1995, 36, 9043.
(c) Yamazaki, S.; Sugiura, H.; Ohashi, S.; Ishizuka, K.; Saimu,
R.; Mikata, Y.; Ogawa, A. J. Org. Chem. 2016, 81, 10863.
5. (a) Horak, Y. I.; Lytvyn, R. Z.; Laba, Y.-O. V.; Homza, Y. V.;
Zaytsev, V. P.; Nadirova, M. A.; Nikanorova, T. V.; Zubkov, F.
I.; Varlamov, A. V.; Obushak, M. D. Tetrahedron Lett. 2017, 58,
4103. (b) Zubkov, F. I.; Zaytsev, V. P.; Mertsalov, D. F.;
Nikitina, E. V.; Horak, Y. I.; Lytvyn, R. Z.; Homza, Y. V.;
Obushak, M. D.; Dorovatovskii, P. V.; Khrustalev, V. N.;
Varlamov, A. V. Tetrahedron 2016, 72, 2239. (c) Horak, Y. I.;
Lytvyn, R. Z.; Homza, Y. V.; Zaytsev, V. P.; Mertsalov, D. F.;
Babkina, M. N.; Nikitina, E. V.; Lis, T.; Kinzhybalo, V.;
Matiychuk, V. S.; Zubkov, F. I.; Varlamov, A. V.; Obushak, M.
D. Tetrahedron Lett. 2015, 56, 4499.
Figure 1. Molecular structures of adduct 13f. Displacement
ellipsoids are shown at the 10% probability level.6
In
conclusion,
the
reaction
between
N-aryl-3-
phenylallylamines and maleic anhydride unexpectedly revealed
that the tandem N-acylation/ IMDAV reaction does not stop at
the formation of hexahydrobenzo[f]isoindoles, but continues via
the stereoselective Alder-ene reaction leading to polysubstituted
hydrogenated benzo[f]isoindole-4-carboxylic acids, some of
which exhibit antiviral activity against the H1N1 influenza virus.
6. The colorless crystal of 13f (C40H38N2O8, M = 674.72) is
triclinic, space group P-1, a = 11.993(4) Å, b = 12.821(5) Å, c =
13.603(5) Å, α = 85.446(1)°, β = 63.883(1)°, γ = 66.635(1)°, V =
1712.39(11) Å3, Z = 2, T = 293 K, μ(MoKα) = 0.009 mm-1, dcalc
=
1.309 g/cm3. 26148 total reflections were measured (4.55° ≤ 2Θ
≤ 51°), 6317 unique reflections (Rint = 0.0514, Rsigma = 0.0382)
which were used in all calculations. The final R1 was 0.0638 (I >
2σ (I)) and wR2 was 0.1769 (all data).
Acknowledgments
7. Lin, D.; Li, F.; Wu, Q.; Xie, X.; Wu, W.; Wu, J.; Chen, Q.;
Liu, S.; He, J. Sci. Rep. 2016, 6, 22790.
8. Hussain, M.; Galvin, H. D.; Haw, T. Y.; Nutsford, A. N.;
Husain, M. Infect. Drug Resist. 2017, 20, 121.
The publication was prepared with the support of the “RUDN
University Program 5-100”, by the grant INT/RUS/RFBR/P-294,
and by the grant RFBR 17-53-45016.
9. Krajczyk, A.; Kulinska, K.; Kulinski, T.; Hurst, B. L.; Day, C.
W.; Smee, D. F.; Ostrowski, T.; Januszczyk, P.; Zeidler, J.
Antivir. Chem. Chemother. 2014, 23, 161.
References and notes
1. For recent examples of the intramolecular Diels-Alder reaction
involving a styrene moiety, see: (a) Yang, B.; Lu, Z. J. Org.
Chem. 2016, 81, 7288. (b) Kocsis, L. S.; Kagalwala, H. N.;
Mutto, S.; Godugu, B.; Bernhard, S.; Tantillo, D. J.; Brummond,
K. M. J. Org. Chem. 2015, 80, 11686. (c) Kim, K. H.; Lim, J.
W.; Moon, H. R.; Kim, J. N. Bull. Korean Chem. Soc. 2014, 35,
3254. (d) See a review by Parvatkar, P. T.; Kadam, H. K. Tilve,
S. G. Tetrahedron 2014, 70, 2857, and the references cited
therein. (e) Park, J.-E.; Lee, J.; Seo, S.-Y.; Shin, D. Tetrahedron
Lett. 2014, 55, 818. (f) Benedetti, E.; Veliz, A. B. E.; Charpenay,
Electronic supplementary information (ESI) for this paper is
available: single-crystal X-ray description for 13f, detailed
synthetic procedures and spectral data for compounds 11-13. See
DOI:

5
One-step and diastereoselective approach for benzo[f]isoindole-4-carboxylic acids.
Previously unknown tandem N-acylation/ IMDAV / Alder-ene reaction was discovered.
Benzo[f]isoindoles display antiviral activity against the influenza virus H1N1