Different addition modes of cyclopentadiene and furan at methylidene(thio)hydantoins

Article abstract of DOI:10.1016/j.mencom.2021.03.034

3-Methylidene-5-phenylhydantoin and 3-methylidene-5-phenylthiohydantoin react with cyclopentadiene forming spirocyclic Diels–Alder adducts. In contrast, their reactions with furan in the presence of AlCl₃ give the products of the furan α-amidoa

Full text of DOI:10.1016/j.mencom.2021.03.034

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 246–247
Different addition modes of cyclopentadiene
and furan at methylidene(thio)hydantoins
Dmitry E. Shybanov, Maxim E. Kukushkin, Viktor A. Tafeenko, Nikolai V. Zyk,
Yuri K. Grishin, Vitaly A. Roznyatovsky and Elena K. Beloglazkina*
Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
E-mail: bel@org.chem.msu.ru
DOI: 10.1016/j.mencom.2021.03.034
Ph
N
Ph
N
3-Methylidene-5-phenylhydantoin and 3-methylidene-5-
phenylthiohydantoin react with cyclopentadiene forming
spirocyclic Diels–Alder adducts. In contrast, their reactions
with furan in the presence of AlCl3 give the products of the
furan α-amidoalkylation.
Ph
N
O
X
X
O
O
X
O
Diels–Alder
reaction
NH
Amido-
alkylation
NH
Me
NH
X = O, S
O
Keywords: hydantoins, thiohydantoins, Diels–Alder reaction, α-amidoalkylation, X-ray.
Hydantoinandthiohydantoinderivativesareknownasbiologically
active substances with antidepressant,1 anticonvulsant,2 anti-
inflammatory,3 anti-fibrolytic,4 anticancer,5 antibacterial6 and
antimalarials7 activities. A promising way for their modification is
introduction of additional spiro fused fragments that would limit
the conformational mobility of the molecule and can lead to a
significant increase in biological activity.8–12 The products of the
Diels–Alder reactions of methylideneimidazolones with cyclic
dienes potentially allow one to obtain spiro fused structures with
a conformationally rigid bicyclic framework containing a reactive
C=C double bond, which opens the way for further modification
of target compounds. Taking this into consideration, we herein
investigated the possibility of synthesizing (thio)hydantoin and
spiro derivatives containing cage fragments by the reactions of
5-methylidene(thio)hydantoins with carbo- and heterocyclic
dienes such as cyclopentadiene and furan.
Starting methylideneimidazolones 1 and 2 were obtained as
described.13,14 Their reactions with cyclopentadiene were
performed by refluxing in methanol for ~6 h with the complete
conversion of the starting imidazolones. As a result, the Diels–
Alder adducts 3 and 4 were obtained in good yields (Scheme 1).
The reaction conditions (the reactant ratio, solvent and
temperature) were optimized with hydantoin 1 as the model
substrate. It turned out to be optimal to use an 8-fold excess of
the diene in boiling chloroform, benzene, methanol or ethanol; in
DMSO, acetonitrile, acetone or ethyl acetate, the reaction
proceeded slowly or almost did not take place.
respectively, which could be separated by column chroma-
tography. As for other methylideneimidazolone derivatives,15
adducts 3a, 4a with the amide nitrogen of imidazolone in the
endo position of the norbornene ring are predominantly formed.
1H NMR spectra of compounds 3a, 4a contain characteristic
double doublets for HC=CH protons in the range of 6.2–6.6 ppm
while similar protons of minor isomers 3b, 4b resonate in the
range of 6.1–6.4 ppm.
The structure of the main reaction product with
cyclopentadiene 3a was proven by X-ray diffraction analysis.†
Dihedral angle between the planes of the cycles at spiro junction
are close to 80° while hydantoin five-membered cycle is nearly
planar (Figure 1).
In contrast to cyclopentadiene, furan did not undergo the
[4+2]-cycloaddition reactions with compounds 1 and 2,
apparently due to the relative stability of the furan heteroaromatic
system. We tested several Lewis acids such as BF3 ·Et2O, AlCl3
and CuCl2 as possible catalysts for this Diels–Alder reaction.
When using CuCl2, the reaction did not proceed even with a
100-fold excess of furan while in the presence of BF3 ·Et2O
furan was rapidly decomposed. The use of AlCl3 with the
simultaneous mixing of all the reactants also caused gradual
†
Crystal data for 3a. C15H14N2O2 (M = 254.28), triclinic, space group
–
P1 at 293(2) K, a = 6.2292(3), b = 9.5107(5) and c = 22.7896(8) Å,
a = 78.582(3)°, b = 82.750(4)°, g = 76.124(4)°, V = 1280.40(11) Å3,
Z = 4, dcalc = 1.319 g cm–3, μ(MoKα) = 0.722 mm–1, F(000) = 536. Total
of 14894 reflections were collected and 4837 independent reflections
with I > 2s(I), Rint = 0.0720 were used in the refinement, which
converged to wR2 = 0.1239, GOOF 1.086 for all independent reflections
[R1 = 0.0500 was calculated for 3218 reflections with I > 2s(I)]. The
Reactions with cyclopentadiene for each of dienophile 1, 2
afforded two diastereomeric products 3a, 4a and 3b, 4b,
measurements were performed on
a STOE diffractometer with
Ph
N
Ph
N
Ph
N
Pilatus100 K detector and CuKα radiation (l = 1.54186 Å). The structure
was solved by direct methods, and the non-hydrogen atoms were located
from the trial structure and then refined anisotropically with SHELXTL
using full-matrix least-squares procedures based on F2 values. Hydrogen
atom positions were fixed geometrically at calculated distances and
allowed to ride on the parent atoms.
CCDC 2040280 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
X
X
O
O
i
X
O
+
+
NH
NH
NH
1 X = O
2 X = S
3b X = O, 9%
4b X = S, 8%
3a X = O, 81%
4a X = S, 79%
Scheme 1 Reagents and conditions: i, MeOH, reflux, 6 h.
© 2021 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 246 –

Mendeleev Commun., 2021, 31, 246–247
Ph
N
Oꢀ1Aꢁ
Ph
N
CꢀꢇAꢁ
CꢀꢈAꢁ
X
O
CꢀꢆAꢁ
Cꢀ2Aꢁ
Nꢀ2Aꢁ
X
O
i
Cꢀ1ꢅAꢁ
ii
N
Cꢀ1ꢄAꢁ
1
Cꢀ10Aꢁ
CꢀꢃAꢁ
Ac
99%
traces
Cꢀ1ꢃAꢁ
N
Nꢀ1Aꢁ
CꢀꢂAꢁ
CꢀꢄAꢁ
Cꢀ11Aꢁ
CꢀꢅAꢁ
Ac
Cꢀ12Aꢁ
O
Cꢀ1ꢂAꢁ
Oꢀ2Aꢁ
8
7
Figure 1 Molecular structure of compound 3a (thermal ellipsoids are
given with 40% probability).
Scheme 3 Reagents and conditions: i, Ac2O, NEt3, DMAP, CH2Cl2, room
temperature, 24 h; ii, furan, AlCl3, CH2Cl2, room temperature, 24 h.
decomposition, however short keeping of the furan-AlCl3
mixture followed by the addition of methylideneimidazolones
gave adducts 5a, 6a in moderate yields (Scheme 2). Apparently,
in this way furan in the reaction with compounds 1, 2 underwent
α-amidoalkylation instead of expected cycloaddition. It can be
assumed that the reaction proceeds according to the mechanism
described for the reactions of α-amidoacrylates with five-
membered heterocycles.16 Under the action of Lewis acid, the
enamine–imine equilibrium of methylideneimidazolones shifts
towards the imine forms 1', 2' (see Scheme 2), which effectively
interact with activated furan–AlCl3 complex to form the
α-amidoalkylation products 5a, 6a. In the NMR spectra of the
reaction mixtures, the trace amounts of the Michael addition
products 5b, 6b formed from the predominant enamine tautomer
were also detected. The comparatively lower yields of products
6 obtained from methylidenethiohydantoin 2 relatively to its
oxygen analogue 1 may be associated with the weaker acceptor
properties of the double C=S bond and the possible partial
hydrolysis of the thioamide fragment in the course of the final
aqueous work up.
whereas the reaction with furan in the presence of a Lewis acid
(AlCl3) proceeds predominantly as α-amidoalkylation of furan.
This work was supported by the Russian Science Foundation
(grant no. 20-73-00234) and Russian Foundation for Basic
Research (grant no. 19-03-00201). This work in part of NMR
and X-ray study was supported by the M.V. Lomonosov Moscow
State University Program of Development.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2021.03.034.
References
1 F. L. Wessels, T. J. Schwan and S. F. Pong, J. Pharm. Sci., 1980, 69,
1102.
2 M. Meusel and M. Gütschow, Org. Prep. Proced. Int., 2004, 36, 391.
3 S. M. Sondhi, J. Singh, A. Kumar, H. Jamal and P. P. Gupta, Eur.
J. Med. Chem., 2009, 44, 1010.
4 N. Teno, K. Gohda, K. Wanaka, Y. Tsuda, T. Sueda, Y. Yamashita and
T. Otsubo, Bioorg. Med. Chem., 2014, 22, 2339.
In the 1H NMR spectra of products 5a and 6a, the characteristic
singlets for the methyl group at ~1.9 ppm, as well as two doublets
and a double doublets for α-substituted furans were observed.
Michael adducts 5b and 6b are characterized by the ABX spin
system in the region of 3.0–4.5 ppm.
To confirm the proposed mechanism of amidoalkylation, we
synthesized an acylated methylidenehydantoin derivative 7
incapable of imine–enamine tautomerism (Scheme 3). Indeed,
compound 7 did not essentially react with furan in the presence
of AlCl3; only the inseparable traces of the Michael adduct 8
were detected in the NMR spectrum of the crude material while
only the starting imidazolone 1 and furan polymerization
products could be ultimately isolated.
5 M. Lamothe, M. Lannuzel and M. Perez, J. Comb. Chem., 2002, 4, 73.
6 J. Handzlik, E. Szymanska, J. Chevalier, E. Otrebska, K. Kiec-
Kononowicz, J.-M. Pagès and S. Alibert, Eur. J. Med. Chem., 2011, 46,
5807.
7 M. J. Meyers, E. J. Anderson, S. A. McNitt, T. M. Krenning, M. Singh,
J. Xu, W. Zeng, L. Qin, W. Xu, S. Zhao, L. Qin, C. S. Eickhoff, J. Oliva,
M.A. Campbell, S. D.Arnett, M. J. Prinsen, D. W. Griggs, P. G. Ruminski,
D. E. Goldberg, K. Ding, X. Liu, Z. Tu, M. D. Tortorella, F. M. Sverdrup
and X. Chen, Bioorg. Med. Chem., 2015, 23, 5144.
8 Y. A. Ivanenkov, S. V. Vasilevski, E. K. Beloglazkina, M. E. Kukushkin,
A. E. Machulkin, M. S. Veselov, N. V. Chufarova, E. S. Chernyagina,
A. S. Vanzcool, N. V. Zyk, D. A. Skvortsov, A. A. Khutornenko,
A. L. Rusanov, A. G. Tonevitsky, O. A. Dontsova and A. G. Majouga,
Bioorg. Med. Chem. Lett., 2015, 25, 404.
9 A. A. Beloglazkina, D. A. Skvortsov, V. A. Tafeenko, A. G. Majouga,
N. V. Zyk and E. K. Beloglazkina, Russ. Chem. Bull., Int. Ed., 2018, 67,
562 (Izv. Akad. Nauk, Ser. Khim., 2018, 562).
10 A. A. Beloglazkina, N. A. Karpov, S. R. Mefedova, V. S. Polyakov,
D. A. Skvortsov, M. A. Kalinina, V. A. Tafeenko, A. G. Majouga,
N. V. Zyk and E. K. Beloglazkina, Russ. Chem. Bull., Int. Ed., 2019, 68,
1006 (Izv. Akad. Nauk, Ser. Khim., 2019, 1006).
11 M. E. Kukushkin, D. A. Skvortsov, M. A. Kalinina, V. A. Tafeenko,
V. V. Burmistrov, G. M. Butov, N. V. Zyk, A. G. Majouga and
E. K. Beloglazkina, Phosphorus, Sulfur Silicon Relat. Elem., 2020, 195,
544.
12 A. Beloglazkina, A. Barashkin, V. Polyakov, G. Kotovsky, N. Karpov,
S. Mefedova, B. Zagribelny, Y. Ivanenkov, M. Kalinina, D. Skvortsov,
V. Tafeenko, N. Zyk, A. Majouga and E. Beloglazkina, Chem.
Heterocycl. Compd., 2020, 56, 747 (Khim. Geterotsikl. Soedin., 2020,
56, 747).
In summary, the reactions of 5-methylidene-2-chalcogeno-
imidazolidin-4-ones with cyclic dienes, viz. cyclopentadiene and
furan, proceed in different ways. With cyclopentadiene, tricyclic
cage structures with a spiro junction of cycles are formed
Ph
N
Ph
N
tautomerization
X
X
O
O
NH
1, 2
N
Me
1', 2'
Ph
N
Ph
N
X
X
O
O
13 N. Abe, F. Fujisaki and K. Sumoto, Chem. Pharm. Bull., 1998, 46, 142.
14 F. Fujisaki, K. Shoji and K. Sumoto, Heterocycles, 2009, 78, 213.
15 T. A. Cernak and J. L. Gleason, J. Org. Chem., 2008, 73, 102.
16 A. la Hoz, A. Diaz-Ortiz, M. V. Gómez, J. A. Mayoral, A. Moreno,
A. M. Sánchez-Migallón and E. Vázquez, Tetrahedron, 2001, 57, 5421.
i
NH
NH
+
Me
O
O
5a X = O, 51%
6a X = S, 25%
5b X = O, traces
6b X = S, traces
Scheme 2 Reagents and conditions: i, furan, AlCl3, CH2Cl2, room
temperature, 24 h.
Received: 24th November 2020; Com. 20/6376
– 247 –