Variability of the Transformations of 4-Hydroxy-6-methyl-2H-pyran-2-one under Modified Biginelli Reaction Conditions

Article abstract of DOI:10.1134/S1070428018010098

A modified version of the three-component Biginelli reaction of 4-hydroxy-6-methyl-2H-pyran-2-one with aromatic aldehydes in urea under conventional heating and microwave activation has been studied. Depending on the order of addition of the reactants, su

Full text of DOI:10.1134/S1070428018010098

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 1, pp. 102–106. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © I.V. Strashilina, O.A. Mazhukina, O.V. Fedotova, 2018, published in Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 1,
pp. 103–106.
Variability of the Transformations
of 4-Hydroxy-6-methyl-2H-pyran-2-one under Modified
Biginelli Reaction Conditions
I. V. Strashilina,* O. A. Mazhukina, and O. V. Fedotova
Chernyshevskii Saratov National Research State University, ul. Astrakhanskaya 83, Saratov, 410012 Russia
*e-mail: irinastrashilina@mail.ru
Received July 5, 2017
Abstract—A modified version of the three-component Biginelli reaction of 4-hydroxy-6-methyl-2H-pyran-2-
one with aromatic aldehydes in urea under conventional heating and microwave activation has been studied.
Depending on the order of addition of the reactants, substituted (pyrano)chromenones, 10-amino-4a-hydroxy-
dihydropyranochromen-2-one, and 3-[amino(phenyl)methyl]-4-hydroxypyran-2-one were obtained.
DOI: 10.1134/S1070428018010098
Natural and synthetic compounds containing
a 2H-pyran-2-one fragment exhibit a broad spectrum
of biological activity, in particular antimicrobial [1],
antitumor [2–4], antitubercular [5], and enzyme inhibi-
tory activities [6]. This makes them promising can-
didates for use in medical practice. Synthesis of hybrid
structures containing both 2H-pyran-2-one and other
pharmacophoric fragments could considerably extend
the scope of their application.
In recent years, one-pot multicomponent syntheses
involving three and more reactants are increasingly
used for the construction of complex heterocyclic
systems. An example of such syntheses is the Biginelli
reaction. The classical Biginelli reaction is an acid-
catalyzed one-pot cyclocondensation of β-keto esters
with aldehydes and urea, leading to the formation of
substituted 3,4-dihydropyrimidinones [7]. This reac-
tion is a multistep process which can follow several
alternative paths [8, 9].
In this work we studied a modified version of the
Biginelli reaction of a cyclic β-keto ester, 4-hydroxy-6-
methyl-2H-pyran-2-one (1), with salicylaldehyde (2)
and urea (3). However, no classical Biginelli reaction
products were obtained. Heating of a mixture of equi-
molar amounts of compounds 1–3 in boiling ethanol in
the presence of HCl afforded 1-(2-oxo-2H-chromen-3-
yl)butane-1,3-dione (4) and 10-(4-hydroxy-6-methyl-
2-oxo-2H-pyran-3-yl)-3-methylpyrano[4,3-b]chromen-
1(10H)-one (5) which were formed according to the
mechanism described in [10] (Scheme 1). In this case,
urea was not involved in the condensation, in contrast
to the data of [11, 12] where 1-(2-oxo-2H-chromen-3-
yl)butane-1,3-dione (4) was reported to react with
ureas, yielding chromenopyrimidine and chromeno-
quinazoline derivatives. The structure of 4 and 5 was
1
confirmed by H and 13C NMR spectra and was con-
sistent with the results given in [10, 12].
Modified versions of the Biginelli reaction with the
use of various catalysts and conditions have been pro-
posed. For example, Lewis acids as catalyst and micro-
wave activation made it possible to significantly
shorten the reaction time [13, 14].
The reaction of 4-hydroxy-6-methyl-2H-pyran-2-
one (1) with salicylaldehyde and urea in the presence
of zinc chloride under microwave irradiation gave 44%
of N-[3-(4a-hydroxy-3-methyl-1-oxo-1,4a-dihydro-
pyrano[4,3-b]chromen-10-yl)-6-methyl-2-oxo-2H-
pyran-4-yl]urea (6) as the only product. Compound 6
is likely to be formed via nucleophilic substitution at
the carbonyl group of the oxo tautomer of 5. The
above results suggest initial condensation of 1 with
aldehyde and subsequent formation of 5 through hemi-
ketal intermediate.
1
The H NMR spectrum of 6 contained a six-proton
singlet at δ 2.08 ppm from the methyl protons, a multi-
plet at δ 6.61–7.60 ppm due to aromatic protons, and
two singlets at δ 5.85 and 8.44 ppm due to vinylic 4-H
and 5′-H protons, respectively, of the pyran fragments.
The downfield position of the 5′-H signal is deter-
102

VARIABILITY OF THE TRANSFORMATIONS OF 4-HYDROXY-6-METHYL-...
103
Scheme 1.
O
Me
OH
O
O
O
HCl, EtOH
78°C
O
+
O
O
Me
O
Me
O
OH
O
CHO
4
5
OH
O
+
+
O
H2N
NH2
Me
O
H2N
Me
NH
O
O
O
OH
1
2
3
ZnCl2, MW
4
5'
Me
O O
6
mined by conjugation with the fused system. This is
consistent with two-dimensional heteronuclear cor-
relation data (HMQC, HMBC). The HMQC spectrum
of 6 showed cross-peaks at δ/δC 5.85/99.7 and
8.44/125.0 ppm for vinylic protons of the pyranone
fragments. Furthermore, in the HMBC spectrum of 6
we observed a cross-peak δ/δC 8.44/151.9 ppm due to
correlation between 5′-H and carbonyl carbon atom of
the urea fragment. The hemiketal structure of the
chromene fragment follows from the cross-peak
δ/δC 2.21/99.7 ppm in the HMBC spectrum (coupling
between the hemiketal hydroxy proton and vinylic
carbon atom). Proton of the secondary amino group
resonated as a broadened singlet at δ 10.89 ppm, and
the primary amino group gave a singlet at δ 11.54 ppm.
with 4-hydroxy-6-methyl-2H-pyran-2-one (1) led to
the formation of previously unknown 10-amino-4a-hy-
droxy-3-methyl-10,10a-dihydropyrano[4,3-b]chromen-
1(4aH)-one (8) in 69% yield (Scheme 2).
1
The H NMR spectrum of 8 showed a three-proton
singlet at δ 2.27 ppm due to methyl group, a multiplet
of aromatic protons in the region δ 6.88–7.77 ppm,
a singlet at δ 6.13 ppm due to vinylic proton, and two
CH doublets at δ 5.12 (J = 8 Hz) and 5.91 ppm (J =
8 Hz). The 4a-OH proton resonated as a singlet at
δ 3.71 ppm, and the two-proton singlet at δ 2.11 ppm
was assigned to the amino group. In addition, down-
field signals of the vinylic proton (δ 8.66 ppm, s),
phenolic hydroxy group (δ 8.95 ppm, s) and =NH
proton (δ 10.18 ppm, br.s) were observed in the
1H NMR spectrum; these findings, in combination with
the intensity of the aromatic multiplet, suggest the
presence of an impurity of 7, which confirms the
proposed reaction sequence.
In order to exclude initial condensation of salicyl-
aldehyde with 4-hydroxy-6-methyl-2H-pyran-2-one,
the former was reacted first with urea. Prolonged
heating (up to 7 h) promoted thermal decomposition of
urea to ammonia which reacted with salicylaldehyde to
give 2-iminomethylphenol 7, and reaction of the latter
In order to confirm the conclusion on the effect of
the ortho substituent in the aldehyde component on the
Scheme 2.
O
∆
NH3
+
CO2
H2N
NH2
3
OH
NH2
O
(1)
CHO
OH
NH3
O
NH
Me
O
O
OH
O
Me
OH
2
7
8
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STRASHILINA et al.
104
Scheme 3.
OH
NH2
Ph
O
O
NH2
Ph
HCl, EtOH
78°C
Me
O
O
Me
O
OH
O
CHO
9a
9b
O
+
+
H2N
NH2
Me
O
OH
O
OH
O
1
3
ZnCl2, MW
Me
Me
O O
10
reaction direction, the condensation was carried out
with benzaldehyde instead of salicylaldehyde. As con-
sidered above, the thermal reaction involves condensa-
tion of benzaldehyde with heterocyclic substrate 1 to
form chalcone type intermediate whose reaction with
ammonia (generated by decomposition of urea) yields
3-[amino(phenyl)methyl]-4-hydroxy-6-methyl-2H-
pyran-2-one (9) which is difficult to obtain under dif-
ferent conditions (Scheme 3).
ucts are capable of reacting with urea. However, the
path through the formation of aldehyde imine and its
subsequent reaction with 1,3-diketone is also possible,
which demonstrates diversity of the examined multi-
component transformation.
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded at
20–25°C on a Varian 400 spectrometer at 400 and
100 MHz, respectively, using CDCl3 as solvent and
tetramethylsilane as internal standard. The reactions
were carried out in an Anton Paar Monowave 300
microwave reactor (constant temperature mode). The
reaction temperature was controlled with a fiber-optic
temperature sensor (850 W). The elemental analyses
were obtained on a Vario Micro Cube analyzer. The
progress of reactions was monitored, and the products
were identified and checked for purity, by TLC, 1H and
13C NMR, and HMQC and HMBC methods. Silufol
UV-254 plates were used for TLC (eluent hexane–
ethyl acetate–chloroform, 3:1:1); spots were visual-
ized by treatment with iodine vapor and under ultra-
violet light.
Microwave-assisted reaction of 4-hydroxy-6-
methyl-2H-pyran-2-one with benzaldehyde and urea in
the presence of zinc chloride afforded 3,3′-(phenyl-
methylene)bis(4-hydroxy-6-methyl-2H-pyran-2-one)
(10) (Scheme 3). Urea does not participate in the
formation of 10. The product structure was determined
1
13
on the basis of the H and C NMR data, which were
in agreement with those given in [15].
1
The H NMR spectrum of substituted 2H-pyran-2-
one 9 contained a singlet at δ 1.27 ppm from two
protons of the amino group, a signal of the methyl
group at δ 2.20 ppm, a multiplet of aromatic protons in
the region δ 6.79–8.07 ppm, and a singlet of the vinylic
proton at δ 6.08 ppm. Also, a broadened singlet was
observed at δ 10.95 ppm, which was assigned to enolic
OH proton involved in intramolecular hydrogen bond
with the amino group. Simultaneously, two CH dou-
blets at δ 4.10 and 5.80 ppm with similar coupling
constants (J = 8 Hz) were present. These findings
suggest that compound 9 in solution exists as a mixture
of enol and ketone tautomers 9a and 9b.
1-(2-Oxo-2H-chromen-3-yl)butane-1,3-dione (4)
and 10-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-
3-methyl-1H,10H-pyrano[4,3-b]chromen-1-one (5).
A mixture of 0.5 g (3.9 mmol) of 4-hydroxy-6-
methylpyran-2-one (1), 0.41 mL (0.48 g, 3.9 mmol) of
2-hydroxybenzaldehyde (2), 0.24 g (3.9 mmol) of urea
(3), 15 mL of ethanol, and several drops of concen-
trated aqueous HCl was refluxed for 24 h. The color-
less crystals of 5 were filtered off, washed with hot
ethanol, and dried. Yield 0.26 g (4%), mp 248–250°C
Thus, the reaction of 4-hydroxy-6-methyl-2H-pyr-
an-2-one with aromatic aldehydes and urea preferen-
tially involves the condensation of the methylene and
carbonyl components, and only the condensation prod-
1
[10]. H NMR spectrum, δ, ppm: 2.12 s (3H, CH3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 1 2018

VARIABILITY OF THE TRANSFORMATIONS OF 4-HYDROXY-6-METHYL-...
105
2.29 s (3H, CH3), 5.08 s (1H, CH), 5.92 s (1H, =CH),
6.18 s (1H, =CH), 6.96–7.26 m (4H, Harom), 9.99 br.s
(1H, OH). 13C NMR spectrum, δC, ppm: 19.6 (C13′),
19.8 (C13), 39.3 (C10), 100.8 (C4), 102.1 (C5′), 107.9,
108.1, 115.9, 116.3, 119.4, 127.8 (Carom), 122.3 (C3′),
123.1 (C10a), 129.7 (C4a), 130.0 (C4′), 145.3 (C6′), 145.6
(C3), 161.6 (C1), 164.8 (C2′). Found, %: C 67.21;
H 4.48. C19H14O6. Calculated, %: C 67.45; H 4.17.
3.71 s (1H, OH), 5.12 d (1H, CH, J = 8 Hz), 5.91 d
(1H, CH, J = 8 Hz), 6.88–7.77 m (8H, Harom), 8.66 s
(1H, =CH), 8.95 s (1H, OH), 10.18 br.s (1H, =NH).
Found, %: C 64.08; H 4.92; N 5.37. C13H13NO4.
Calculated, %: C 63.67; H 4.52; N 5.71.
3-[Amino(phenyl)methyl]-4-hydroxy-6-methyl-
2H-pyran-2-one (9) was synthesized as described
above for compound 4 from 0.5 g (4.5 mmol) of 1,
0.6 mL (0.48 g, 4.5 mmol) of benzaldehyde, and 0.27 g
(4.5 mmol) of urea (3) in the presence of concentrated
aqueous HCl; reaction time 32 h. Yield 0.87 g (84%),
The filtrate was cooled, and the yellow–orange
crystals of 4 were filtered off, washed with ethanol,
and dried. Yield 1.45 g (62%), mp 151–152°C [12].
1H NMR spectrum, δ, ppm: 2.20 s (3H, CH3), 6.85 s
(1H, =CH), 7.35–7.96 m (4H, Harom), 8.76 s (1H,
=CH), 15.96 s (1H, OH). 13C NMR spectrum, δC, ppm:
27.5 (C4′), 101.6 (C3), 116.6, 118.5, 120.6, 124.9,
129.5, 134.0 (Carom), 116.9 (C4), 125.3 (C2′), 154.4
(C3′), 158.0 (C2), 171.9 (C1′). Found, %: C 68.13;
H 4.55. C13H10O4. Calculated, %: C 67.82; H 4.38.
1
red crystals, mp 156–158°C. H NMR spectrum, δ,
ppm: 1.27 s (2H, NH2), 2.20 s (3H, CH3), 4.10 d (1H,
CH, J = 8 Hz), 5.80 d (1H, CH, J = 8 Hz), 6.08 s (1H,
=CH), 6.79–8.07 m (5H, Harom), 10.95 br.s (1H, OH).
13C NMR spectrum, δC, ppm: 19.7 (C14), 34.7 (C7),
103.2 (C5), 104.6 (C3), 126.4, 126.6, 126.7, 128.3,
128.5, 130.1 (Carom), 135.4 (C6), 161.1 (C4), 168.8 (C2).
Found, %: C 67.89; H 5.84; N 5.98. C13H13NO3. Cal-
culated, %: C 67.52; H 5.67; N 6.06.
N-[3-(4a-Hydroxy-3-methyl-1-oxo-1H,4aH-
pyrano[4,3-b]chromen-10-yl)-6-methyl-2-oxo-2H-
pyran-4-yl]urea (6). A porcelain dish was charged
with 0.5 g (3.9 mmol) of compound 1, 0.41 mL
(0.48 g, 3.9 mmol) of 2-hydroxybenzaldehyde (2),
0.24 g (3.9 mmol) of urea (3), and several drops of
a 10% solution of zinc chloride in ethanol. The mixture
was subjected to microwave irradiation over a period
of 3 h. When the reaction was complete, the yellow
crystals of 6 were washed with water and dried. Yield
3,3′-(Phenylmethylene)bis(4-hydroxy-6-methyl-
2H-pyran-2-one) (10) was synthesized as described
above for compound 6 from 0.5 g (3.9 mmol) of 1,
0.46 mL (0.48 g, 3.9 mmol) of benzaldehyde, and
0.24 g (3.9 mmol) of urea in the presence of
10% ethanolic ZnCl2 under microwave irradiation over
a period of 2 h. The colorless crystals were washed
with ethanol and dried. Yield 0.61 g (65%), mp 214–
1
1
215°C [15]. H NMR spectrum, δ, ppm: 2.29 s (6H,
0.22 g (44%), mp 180–182°C. H NMR spectrum, δ,
CH3), 5.76 s (1H, CH), 6.06 s (2H, =CH), 6.97–7.50 m
(5H, Harom), 10.73 s (2H, OH), 10.93 s (1H, OH).
13C NMR spectrum, δC, ppm: 17.9 (C15), 18.3 (C25),
34.0 (C7), 102.4, 103.1 (C5, C5′), 110.2, 110.4 (C3, C3′),
127.4, 127.8, 128.0, 128.2, 128.6, 139.4 (Carom), 143.8,
144.2 (C6, C6′), 160.3, 160.4 (C2, C2′), 166.0, 166.2 (C4,
C4′). Found, %: C 67.33; H 4.58. C19H16O6. Calculated,
%: C 67.05; H 4.84.
ppm: 2.08 s (6H, CH3), 2.10 s (1H, OH), 5.85 s (1H,
=CH), 6.61–7.60 m (4H, Harom), 8.44 s (1H, =CH),
13
10.89 s (1H, NH), 11.54 s (2H, NH2). C NMR spec-
trum, δC, ppm: 19.5 (C13), 19.8 (C13′), 88.6 (C4a), 99.7
(C4), 123.4 (C3′), 125.0 (C5′), 125.1, 126.3, 128.4,
129.5, 130.3, 136.2 (Carom), 128.6 (C10a), 131.2 (C10),
141.7 (C4′), 143.8 (C3), 143.7 (C6′), 163.7 (C1′), 165.2
(C2′), 167.1 (C14). Found, %: C 61.03; H 4.13; N 6.68.
C20H16N2O7. Calculated, %: C 60.61; H 4.07; N 7.07.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 16-03-00730).
10-Amino-4a-hydroxy-3-methyl-10,10a-dihydro-
pyrano[4,3-b]chromen-1(4aH)-one (8). A mixture of
0.94 mL (1.10 g, 9 mmol) of 2-hydroxybenzaldehyde
(2), 0.54 g (9 mmol) of urea (3), and several drops of
concentrated aqueous HCl in ethanol was refluxed
until the initial aldehyde disappeared. Compound 1,
1 g (9 mmol), was added, and the mixture was refluxed
for 20 h at 75°C. When the reaction was complete, the
mixture was evaporated in air, and the orange crystals
of 8 were washed with water and dried. Yield 1.42 g
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