New 1-hetarylfuropyridines and chromenes based on pyridoxal and 4-hydroxycoumarin

Article abstract of DOI:10.1016/j.mencom.2020.11.025

Pyridoxal in the absence of catalyst forms furo[3,4-c]pyridine species (ortho aldehyde and hydroxymethyl groups are involved) which is further transformed into C–C hybrid with 4-hydroxycoumarin. Different products of chromeno-[3′,4′:5,6]pyrano[2,3-c]pyrid

Full text of DOI:10.1016/j.mencom.2020.11.025

Mendeleev
Communications
Mendeleev Commun., 2020, 30, 765–767
New 1-hetarylfuropyridines and chromenes based on pyridoxal
and 4-hydroxycoumarin
a
a
a
b
Alexey V. Trifonov,* Lyudmila K. Kibardina, Alexey B. Dobrynin, Amirjon A. Ali Akhunov,
a
a
Mikhail A. Pudovik and Alexander R. Burilov
a
b
A. E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of the Russian
Academy of Sciences, 420088 Kazan, Russian Federation. E-mail: alexey.trifonov@iopc.ru
Kazan National Research Technological University, 420015 Kazan, Russian Federation
DOI: 10.1016/j.mencom.2020.11.025
Pyridoxal in the absence of catalyst forms furo[3,4-c]pyridine
species (ortho aldehyde and hydroxymethyl groups are
involved) which is further transformed into C–C hybrid
with 4-hydroxycoumarin. Different products of chromeno-
OH
Me
CHO
O
N
CH2OH
O
HO
OH
O
O
HO
+
or Me
O
[3',4':5,6]pyrano[2,3-c]pyridine type are formed when
Me
OH
O
HN
Cl
pyridoxalhydrochlorideormoresophisticated2,4-dihydroxy-
benzaldehyde derivative are applied (herein, ortho aldehyde
and hydroxy groups are involved into heterocyclization).
CH2OH
N
O
O
O
O
Keywords: heterocyclization, electrophilic substitution, furo[3,4-c]pyridines, chromeno[3',4':5,6]pyrano[2,3-c]pyridines, pyridoxal,
chromenes.
At present, a strategy of ‘hybrid’ molecules is employed for
design of new effective drugs.1 We have previously carried out
OH
OEt
O
–3
Me
i
chemical modification of pyridoxal (vitamin B ) through its new
6
HN+
Cl
4,5
cascade reaction with phenols, polyphenols, and pyrazol-5-
OH
OH
O
–
6
one derivatives, which allowed us to accees new types of fused
3
Me
CHO
CH OH O
heterocyclis systems such as furopyridines containing phenolic,
polyphenolic and heterocyclic fragments. With the aim of
expanding the series of heterocyclic compounds, which can
participate in such transformations and form various ‘hybrid’
compounds, we studied herein the reactions of pyridoxal 1 and
its derivatives with 4-hydroxycoumarin 2 whose derivatives are
employed as anticoagulants, antitumor, anti-HIV, antipyretic,
cosmetic, and antithrombotic drugs.7 We supposed that new
+
N
2
1
2
ii
O
O
HO
OH
Me
O
N
–13
4
‘hybrid’ compounds containing furopyridine and coumarin
fragments, as well as the structures featuring phenolic group
along with these fragments can result from such reactions.
Initially, the reaction between pyridoxal 1 and 4-hydroxy-
coumarin 2 was tried in the mixture of ethanol and concentrated
hydrochloric acid by analogy with the synthesis of 1-arylfuro-
Scheme 1 Reagents and conditions: i, 2 (1 equiv.), EtOH (abs.)/HCl,
reflux, 10 h; ii, 2 (1 equiv.), EtOH (abs.), reflux, 10 h, yield of 4 97%.
in the course of the reaction, decreased. Thus, the non-catalytic
reaction of pyridoxal 1 with 4-hydroxycoumarin 2 can afford
only 1:1 adducts in nearly quantitative yield.
4,5
pyridines. However, under these conditions 1-ethoxyfuropyridine
as the product of intramolecular acetalization was mostly formed
Scheme 1, conditions i). The desired 1-hetarylfuropyridine 4 was
3
(
The reaction of pyridoxal hydrochloride 1∙HCl with 1 mol of
4-hydroxycoumarin 2 in EtOH without catalysts gives the
product of 1:2 composition 5 being the first representative
of benzochromenopyranopyridines (Scheme 2, conditions i).
Comparable amounts of side 1-ethoxyfuropyridine 3 were also
formed. Changing the 1∙HCl/2 reactant ratio to 1:2 provided the
preparation of target chromene 5 in high yield (see Scheme 2,
conditions ii). Application of TsOH or piperidine as catalysts
caused little effect on the reaction outcome.
We suggest that the reaction occurs according to the cascade
mechanism and compound 5 is formed through electrophilic
substitution in the position 3 of coumarin, with the formation of
an intermediate biscoumarin derivative of pyridoxal and
subsequent intramolecular dehydration with the participation of
not formed, and 4-hydroxycoumarin 2 remained unchanged.
Luckily, the reaction between 1 and 2 in absolute ethanol in
the absence of HCl afforded new 1-hetarylfuropyridine 4 in 97%
yield (see Scheme 1, conditions ii).
A broad variety of catalysts was previously used for the
derivatization of coumarins, in particular, LiCl, propane-1,2,3-
1
4
15
16
triyl tris(hydrosulfate),
[PySO H]Cl,
Bi(NO ) ∙5H O,
3
3 3 2
choline hydroxide,1 TsOH,18,19 and piperidine.
7
20–22
With the
aim to synthesize bis-coumarins with pyridoxal fragment, we
tried the reactions at a 1/2 ratio of 1:2 in the presence of TsOH
or piperidine, as well as without them. However, the product of
1
:2 ratio was not formed while the yield of compound 4 formed
©
2020 Mendeleev Communications. Published by ELSEVIER B.V.
–
765 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2020, 30, 765–767
OH
Me
CHO
i or ii
OH
+
HN
Cl
1
O
–
CH2OH
CHO
O
HO
∙HCl
O
OH
Me
OH
i or ii or iii
HO
OH
OH
O
OEt
HN+
O
Me
O
Me
–
O
Cl
O
+
HN +
O
O
O
HN+
HO
–
Me
–
6
Cl
7
Cl
3
+
HN
Cl
Scheme 3 Reagents and conditions: i, 2 (2 equiv.), EtOH (abs.), TsOH
(cat.), 78 °C, 3 h, 98%; ii, 2 (2 equiv.), EtOH (abs.), without catalyst, 78 °C,
CH2OH
–
O
O
3
h, 90%; iii, 2 (2 equiv.), EtOH (abs.), piperidine (cat.), 78 °C, 3 h, 86%.
5
Scheme 2 Reagents and conditions: i, 2 (1 equiv.), EtOH (abs.), 78 °C,
structure was assigned on the basis of MALDI mass spectrometry
and H NMR spectroscopy data.
1
1
0 h, yield of 5 46%, yield of 3 54%; ii, 2 (2 equiv.), EtOH (abs.), 78 °C,
0 h, yield of 5 67%, 3 is not formed.
1
To conclude, a preparative synthesis of novel hybrid
hetarylfuropyridines and chromenes containing furopyridine,
coumarin and phenol fragments in the molecule has been
accomplished.
the hydroxyl groups of coumarin and pyridine. The structure of
this compound was confirmed by MALDI mass spectrometry,
H NMR spectroscopy, elemental analysis and X-ray analysis
1
data (Figure 1).
According to X-ray data, compound 5 crystallizes in
monoclinic space group C2/c and there is one independent
molecule of compound 5 and Cl-counterion at axis 2, as well as
DMSO solvent molecule in the unit cell. The bond lengths
are within the range of standard values for this type of
The authors are grateful to the Collective Spectral-Analytical
Center of Physicochemical Studies of Structure, Properties, and
Composition of Substances and Materials of the Federal
Research Center Kazan Scientific Center of RAS for technical
support of the studies. X-ray studies were performed using the
equipment of the Federal Research Center Kazan Scientific
Center of RAS.
bonds.
A
six-membered oxygen-containing heterocycle
adopts ‘C(9)-sofa’
O(20)C(3)C(4)C(9)C(10)C(19)
a
conformation; five-atomic fragment C(4)C(3)O(20)C(19)C(10)
is planar within the range of 0.085 Å and C(9) atom deviates at
Online Supplementary Materials
0
.129(6) Å from the plane. Other heterocycles are planar within
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.11.025.
†
the experimental measurement error.
At the next stage of this study, 4-hydroxycoumarin 2 was
4
reacted with previously prepared polycyclic aldehyde 6 based
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–
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3
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