Unusual transformations of 3-thiocarbamoylchromones

Article abstract of DOI:10.1016/j.tetlet.2020.152202

The reaction of malononitrile with 3-thiocarbamoylchromones was accompanied by rearrangement, resulting in the formation of 2,5-dihydro-1H-chromeno[2,3-b]pyridine-3-carbonitriles or 2-imino-5-oxo-1-phenyl-2,5-dihydro-1H-chromeno[2,3-b]pyridine-3-carbothio

Full text of DOI:10.1016/j.tetlet.2020.152202

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
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Unusual transformations of 3-thiocarbamoylchromones
a
a
b
a
Dmitrii Y. Demin , Artem N. Fakhrutdinov , Igor R. Ilyasov , Tatyana K. Baryshnikova ,
a
a,
⇑
Mikhail M. Krayushkin , Vladimir N. Yarovenko
a
N.D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow, Russian Federation
Department of Chemistry, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russian Federation
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of malononitrile with 3-thiocarbamoylchromones was accompanied by rearrangement,
resulting in the formation of 2,5-dihydro-1H-chromeno[2,3-b]pyridine-3-carbonitriles or 2-imino-5-
oxo-1-phenyl-2,5-dihydro-1H-chromeno[2,3-b]pyridine-3-carbothioamides, depending on the nature of
the substituents in the thiocarbamoyl moiety. This reaction sharply differs from the reaction of malonon-
itrile with 3-carbamoylchromones, which gives coumarino-pyridines.
Received 6 May 2020
Revised 22 June 2020
Accepted 29 June 2020
Available online xxxx
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
3
-Thiocarbamoylchromones
Rearrangements
Malononitrile
Chromeno[2,3-b]pyridines
Introduction
17]. Compounds containing this motif have been studied as
antiproliferative [18], anticancer [19], antitubercular, and antimi-
The diverse reactivity of chromones makes them valuable sub-
strates for the synthesis of various compounds [1–5]. Approaches
based on the reactions of chromones containing electron-with-
drawing substituents in position 3 with nucleophiles, which are
accompanied by domino processes, are widely used to prepare var-
ious products, including heterocyclic structures [6–11]. Previously,
we demonstrated that the presence of N-arylamide functional
groups in 3-carbamoylchromones 1a-c results in the formation of
coumarino-pyridines 2a-c upon their reaction with malononitrile
according to the proposed mechanism shown below (Scheme 1)
crobial agents [20], MK-2 inhibitors [21], and DNA ligase inhibi-
tors [22]. Amlexanox, containing a chromeno-pyridine skeleton,
deserves particular attention as an antiallergic and antiulcer
agent, which proved to be efficient for the therapy of type 2 dia-
betes mellitus [23].
Previously, we have developed a novel method for the prepara-
tion of 3-carbamoylchromones 5a, 6a and the scarcely known 3-
thiocarbamoylchromones 5b, 6b. The method included the reac-
tion of o-hydroxyaryleneaminones 3, 4 with isocyanates and isoth-
iocyanates, respectively (Scheme 2) [24,25].
[
12].
The synthetic potential of this approach could be extended by
Our experience of studying 3-carbamoylchromones suggested
that thiocarbonyl groups should also affect the ring transforma-
tions of 3-thiocarbamoylchromones, which takes place after nucle-
ophilic attack and, hence, the structure of products.
using chromones containing substituents in position 3, which
have not been employed for rearrangements, in particular, with
thiocarboxamides, which were not used previously in the chem-
istry of this heterocycle, despite their high synthetic potential.
In view of more diverse reactivity of thioamide groups compared
with amide groups and considering the reactions of nucleophiles
with 3-carbamoylchromones described in our previous publica-
tion [12], we expected that the reactions of 3-thiocar-
bamoylchromones with C-nucleophiles would give other fused
heterocycles, in particular, chromeno[2,3-b]pyridines, which are
of considerable interest as biologically active compounds [13–
Results and discussion
Starting materials 7a-h were synthesized by the reaction of
enaminones with aryl isothiocyanates in DMF according to the
method described in our previous article (Scheme 3) [24].
The present study addresses the reactions of 3-thiocar-
bamoylchromones with malononitrile. These reactions were found
to differ strongly from the above-described reactions which gave
polyfused compounds 2a-c. We demonstrated that malononitrile
in ethanol reacts with 3-thiocarbamoylchromones 7a-c containing
electron-donating substituents on the aryl moieties in the presence
⇑
Corresponding author.
E-mail address: yarovladimir@yandex.ru (V.N. Yarovenko).
https://doi.org/10.1016/j.tetlet.2020.152202
040-4039/Ó 2020 Elsevier Ltd. All rights reserved.
0
Please cite this article as: D. Y. Demin, A. N. Fakhrutdinov, I. R. Ilyasov et al., Unusual transformations of 3-thiocarbamoylchromones, Tetrahedron Letters,
https://doi.org/10.1016/j.tetlet.2020.152202

2
D.Y. Demin et al. / Tetrahedron Letters xxx (xxxx) xxx
Scheme 4. Reaction of 3-thiocarbamoylchromones 7a-c containing electron-
donating substituents with malononitrile. Yields are in brackets.
Scheme 1. Reaction of 3-carbamoylchromones with malononitrile.
Scheme 5. Reaction of 3-thiocarbamoylchromones 7d-g containing electron-with-
drawing substituents with malononitrile. Yields are in brackets.
adds to the nitrile group of the pyridine ring to give primary thioa-
mide 8d-g (Scheme 5).
Scheme 2. Synthesis of 3-carbamoyl/3-thiocarbamoyl chromones.
An intermediate situation is observed for the fluorine-substi-
tuted thiocarbamoylchromone 7h (Scheme 6). In this case, the
reaction affords a mixture of products 8h-1 and 8h-2 in a 3:2 ratio,
which was established from the ratio of proton signals in the 1
NMR spectrum.
H
The structure of compounds 8a-h was proven by mass spec-
1
13
trometry and H and C NMR spectroscopy. For compound 8a,
1
13
two-dimensional
H
C heteronuclear correlation HSQC and
HMBC spectra were recorded, which allowed the assignment of
signals. The presence of a nitrile group in compounds 8a-c was
additionally confirmed by IR spectroscopy (characteristic peak at
À1
1
2
225 cm ). For compound 8d, apart from the heteronuclear spec-
1
Scheme 3. Reaction of enaminones with aryl isothiocyanates.
tra, the H H COSY and NOESY spectra were recorded; the proton
cross-peaks present in these spectra indicated interaction of the
two protons of the thioamide group. No absorption band character-
À1
istic of a nitrile group (ꢀ2225 cm ) was present in the IR spec-
of triethylamine to give 2-imino-5-oxo-1-aryl-2,5-dihydro-1H-
chromeno[2,3-b]pyridine-3-carbonitriles 8a-c (Scheme 4).
The process presumably includes a Michael reaction involving
trum of compounds 8d-g, and no signal of the nitrile carbon
1
3
(
115–117 ppm) was observed in the C NMR spectrum.
the C-2 position of the
retro-Michael reaction with
c
-pyrone ring (A), which is followed by a
-pyrone ring opening (B), rotation
c
around the CAC bond (C), and cyclization involving the hydroxy
group with the elimination of hydrogen sulfide yielding a new pyr-
one ring (D). The final step is heterocyclization giving chromeno
[
2,3-b]pyridines 8a-c. In this case, the cyclization induced by the
hydroxy group is directed towards the thiocarbonyl group, which
is more reactive that the carbonyl group, and is not accompanied
by displacement of the aniline moiety, which takes place in the
reactions
of
N-substituted
3-carbamoylchromones
with
malononitrile.
When electron-withdrawing substituents are present in the
Scheme 6. Reaction of fluorine-substituted thiocarbamoylchromone 7h with
aniline ring of 7d-g, the hydrogen sulfide formed in the reaction
malononitrile.
Please cite this article as: D. Y. Demin, A. N. Fakhrutdinov, I. R. Ilyasov et al., Unusual transformations of 3-thiocarbamoylchromones, Tetrahedron Letters,
https://doi.org/10.1016/j.tetlet.2020.152202

D.Y. Demin et al. / Tetrahedron Letters xxx (xxxx) xxx
3
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Conclusion
We have studied for the first time the reactivity of 3-thiocar-
1
[
bamoylchromones, demonstrated participation of the thiocarbonyl
group in the rearrangements under the action of nucleophiles and
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Declaration of Competing Interest
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The NMR spectra were recorded at the Department of Structural
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Scientific Schools Development Program by Zelinsky Institute of
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Appendix A. Supplementary data
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Supplementary data to this article can be found online at
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Please cite this article as: D. Y. Demin, A. N. Fakhrutdinov, I. R. Ilyasov et al., Unusual transformations of 3-thiocarbamoylchromones, Tetrahedron Letters,
https://doi.org/10.1016/j.tetlet.2020.152202