Oxidative transformations of 4-methylcoumarins using dimethyldioxirane

Article abstract of DOI:10.1002/jhet.826

Efficient regioselective oxidation of the double C-C bond of 4-methylcoumarins with isolated dimethyldioxirane was performed, and related hydroxy and epoxy derivatives were obtained in good yields. All of obtained epoxides and most of hydroxy derivatives are novel compounds. The position of different electron-donating groups attached at the aromatic part of molecule shows significant influence on kinetics and course of the reaction. Copyright

Full text of DOI:10.1002/jhet.826

March 2012
Oxidative Transformations of 4-Methylcoumarins Using
Dimethyldioxirane
261
a,b
Sanja Cavar and Franci Kovac *
ˇb
´
aDepartment of Chemistry, Faculty of Science, University of Sarajevo, 71000 Sarajevo, Bosnia and
Herzegovina
bFaculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana,
Slovenia
*E-mail: franci.fovac@gmail.com or franci.kovac@fkkt.uni-lj.si
Received October 25, 2010
DOI 10.1002/jhet.826
Published online 11 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
Efficient regioselective oxidation of the double CAC bond of 4-methylcoumarins with isolated dime-
thyldioxirane was performed, and related hydroxy and epoxy derivatives were obtained in good yields.
All of obtained epoxides and most of hydroxy derivatives are novel compounds. The position of differ-
ent electron-donating groups attached at the aromatic part of molecule shows significant influence on
kinetics and course of the reaction.
J. Heterocyclic Chem., 49, 261 (2012).
INTRODUCTION
the same molecule. The selectivity is often as high as
those that enzymes are able to achieve.
Coumarins occupy an important place in the realm of
natural products and synthetic organic chemistry. Many
compounds containing the 2H-1-benzopyran-2-one subu-
nit exhibit useful and diverse biological activity and find
their application in pharmaceuticals, fragrances, agro-
chemicals, and insecticides [1,2].
The fact that excess of dimethyldioxirane oxidize the
double CAC bond of few 4-methlycoumarins in regiose-
lective manner has already been reported [12]. Kinetic
analyses demonstrate two independent reaction pathways,
epoxidation and hydroxylation, respectively, which was
also confirmed using kinetic isotope effect methods.
As a part of a continuing effort in our laboratory to-
ward the examinations of oxidation of biologically rele-
vant heterocyclic compounds [9,12], here we report the
synthesis of novel 4-methlycoumarin derivatives,
obtained from their reaction with dimethyldioxirane.
Special attention was paid to reaction kinetics, which
was examined by UV/vis and EPR spectroscopy.
Studying the metabolic pathways of coumarin, it was
found that it is also toxic, due to the formation of cou-
marin-3,4-epoxide, which decomposes to toxic o-
hydroxyphenylacetaldehyde [3–5]. The 4-methylcoumar-
ins are known to be less toxic compared with coumarin
[6–8], but there is lack of data about products of their
reactions with reactive oxygen species. The 4-methyl-
coumarins are also implicated to have several beneficial
pharmacological effects [3,6–9]. It has been noted that
the selective hydroxylation of coumarins by cytochrome
P-450 enzymes and dimethyldioxirane have several fea-
tures in common [10,11]. The reaction of oxidation
involves insertion of oxygen into CAH bonds very effi-
ciently and can discriminate between different sites in
RESULTS AND DISCUSSION
The synthesis of 4-methylcoumarins (1a–j) was car-
ried out according to the slightly modified Pechmann
method [13,14], which involves the condensation of
C
V
2011 HeteroCorporation

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S. Cavar and F. Kovac
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262
Vol 49
different phenols with b-keto esters in the presence of
acidic condensing agents, such as concentrated sulfuric
acid and/or anhydrous aluminum chloride. The yields of
obtained 4-methylcoumarins were, in general, very high
regardless to the structural variations of phenol sub-
strates. The purity of synthesized 4-methylcoumarins
was determined by GC/MS technique and by elemental
analysis. Structural confirmation was done using 1H-
NMR, 13C-NMR, and EI mass spectrometric methods.
The characterizations of these compounds are identical
with the literature reports [15].
A solution of dimethyldioxirane was prepared in pure
acetone, according to the methods described in the liter-
ature [16], and its content was determined using GC/MS
analysis of its reaction with thioanisole [17]. The analy-
sis is done quantitatively by determining the response
factors of the sulfides.
The reactions of 0.12 mol/L isolated dimethyldioxirane
(12 equiv) and selected 4-methylcoumarins (1a–j) were
carried out at room temperature, in dry acetone solution, in
the absence of sunlight and air. The progress of oxidation
was monitored by GC/MS sampling the reaction mixture
every 30 min. The yields of reaction products are calcu-
lated using semiquantitative analysis carried out directly
from peak areas in the GC profile. Detailed chromato-
graphic and spectral study of reaction between selected 4-
methylcoumarins and dimethyldioxirane showed that main
oxidation products are corresponding hydroxy derivatives
(2a–j) and epoxides (3a–j). All of obtained epoxides
[3,4-dihydro-4-methyl-2H-oxireno[c]chromen-2-one (3a),
3,4-dihydro-4,6-dimethyl-2H-oxireno[c]chromen-2-one (3b),
3,4-dihydro-4,7-dimethyl-2H-oxireno[c]chromen-2-one (3d),
3,4-dihydro-4-methyl-6-methoxy-2H-oxireno[c]chromen-
2-one (3e), 6-hydroxy-4-methyl-2H-oxireno[c]chromen-
2-one (3g), and 6-hydroxy-4,7-dimethyl-2H-oxireno[c]
chromen-2-one (3j)], and some of hydroxy derivatives
[3-hydroxy-4-methyl-7-methoxy-2H-chromen-2-one (2f),
3,7-dihydroxy-4-methyl-2H-chromen-2-one (2h), 3,7-dihy-
droxy-4,8-dimethyl-2H-chromen-2-one (2i), and 3,6-
dihydroxy-4,7-dimethyl-2H-chromen-2-one (2j)] are novel
compounds. The proposed reaction route is given in Figure
1. In addition, an experiment under inert atmosphere (ar-
gon) was carried out to double-check if hydroxylation
product is a direct reaction product.
Figure 1. Proposed reaction route of oxidation of 4-methylcoumarins
using dimethyldioxirane.
methylium ion, respectively. Both oxidative products
have the same fragments, but in different abundances
(‘‘Experimental Section’’). All other examined com-
pounds showed the same fragmentation under EI condi-
tions. In general, base peak of hydroxy derivatives is
molecular peak [M]þ, whereas base peak of epoxides is
fragment corresponding to loss of HCO2 following the
loss of methylene group on a pyrone ring (Fig. 2).
The proton NMR of DMSO solution containing the
corresponding epoxide and hydroxide showed resonance
peaks characteristic for hydrogen atoms located at the
aromatic part of coumarin molecule, ranging d 6.83–
7.55 (d). Methyl group at the position C-4 showed sin-
glets ranging d 2.29–2.44, whereas those attached at the
benzene ring were shifted upfield, ranging d 2.03–3.31
(s). Methoxy group located in the aromatic moiety of
the molecule showed singlet chemical shifts at d 3.82–
3.84. Proton from aromatic hydroxy group showed sin-
glet at d 9.22–9.81. All of these chemical shifts can be
compared with those displayed from corresponding cou-
marin substrate and demonstrate that the aromatic part
of the coumarin structures remain unchanged in their
reaction with dimethyldioxirane.
At the end of the reaction, solvent was evaporated
under argon, reaction mixture was dissolved in acetone-
d6 and/or DMSO-d6, and products were determined with
Loss of peak characteristic for hydrogen atoms
located at the 3-positon on pyrone ring proves that oxi-
dation occurs at this position. 4-Methylcoumarin epox-
ides (3a–j) showed chemical shifts ranging d 3.73–3.83
(s), whereas corresponding 3-hydroxy derivatives (2a–j)
displayed singlets ranging d 4.47–5.37. In general, com-
pounds containing aromatic hydroxy group showed sin-
glets for these hydrogen atoms shifted upfield in
1
GC/MS and NMR techniques. The Mass and H-NMR
spectral data of the main products of oxidation are pre-
sented in the ‘‘Experimental Section.’’
The mass spectra of coumarin hydroxy and epoxy
derivatives showed a prominent molecular ion, and frag-
ments corresponding to the loss of HCO [M ꢀ 29]þ and
HCO2 [M ꢀ 44]þ, i.e., benzofuranylium and benzofuran
Journal of Heterocyclic Chemistry
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Oxidative Transformations of 4-Methylcoumarins Using Dimethyldioxirane
263
Figure 2. Proposed rationalization of fragmentation of 3-hydroxy-4,6-dimethyl-2H-chromen-2-one (2b), and 3,4-dihydro-4,6-dimethyl-2H-oxire-
no[c]chromen-2-one (3b) under EI conditions.
comparison with those without hydroxy group. Presented
results are in agreement with those found in literature
[3,12].
As it has been reported [12], kinetic study of the reac-
tion indicates that hydroxy and epoxy derivatives of 4-
methylcoumarins are independently produced. The reac-
tions were proven to be of the second order, overall.
Results show a significant influence of the substituent
position on kinetic rate constants and activation parame-
ters. Some previous studies [18–22] of oxidations of
similar natural products showed that hydroxylation
occurs on the aromatic part of the molecule. Generally,
hydroxylation is much faster than epoxidation, but epox-
idation is energetically favored reaction. Activation
energies span from (16.21 6 0.07) to (38.45 6 0.15) kJ/
kmol for hydroxy derivatives and from (15.06 6 0.10)
to (33.64 6 0.12) kJ/kmol for epoxy derivatives, respec-
tively. Values of logarithm of frequency factor and neg-
ative values of entropy of activation in all examined
cases indicate bimolecular behavior of reaction. Intro-
ducing the methyl group, as a d-donor, on a benzene
ring of a molecule, the reaction rate slightly increases.
Moreover, in the case of 4-methylcoumarins with the p-
donor groups, methoxy and hydroxy group at the aro-
matic part of coumarin structure, reaction rate increases,
especially in the case of hydroxylation.
The epoxide and hydroxy hydrogen atoms were
shifted downfield compared with the H-3 atoms in the
corresponding coumarin molecules (d 5.99–6.92). The
chemical shifts of protons positioned at C-3 atom, for
epoxide and hydroxy derivative, were not detected in
the reaction between dimethyldioxirane and 4,6-di-
methyl-2H-chromen-2-one deuterated at 3-positon (1c).
Moreover, the mass spectra of these two products
showed similarity with mass spectra of oxidation prod-
ucts of 4,6-dimethyl-2H-chromen-2-one (1b), with mass
fragments increased by 1 due to the presence of deute-
rium atom. These outcomes prove the fact that described
epoxides and hydroxy derivatives are the main products
of oxidation of 4-methylcoumarins by dimethyldioxir-
ane. No effort was made to purify the products because
unreacted coumarins served as a convenient internal
standard during sample analysis. It should be noted that
isolation of the main products of oxidation could not be
possible due to its high instability under atmospheric
conditions, especially for epoxides.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Cavar and F. Kovac
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Vol 49
C-centered radical adduct can be explained by elimina-
tion of proton from 4-CH3 group from coumarin. As a
consequence, the obtained methylene radical can be sta-
bilized by resonance [26]. The EPR study confirmed the
fact that dimethyldioxirane probably acts as radical oxy-
gen species, which produce hydroxy derivatives of cor-
responding 4-methylcoumarin.
CONCLUSIONS
Study of the oxyfunctionalization of 4-methylcoumar-
ins by dimethyldioxirane presents a new insight into
introducing an epoxide and hydroxy group to a substrate
molecule under mild conditions. All of obtained epox-
ides and most of hydroxy derivatives are novel
compounds.
The presented findings open a new perspective of the
site-selective oxyfunctionalization of molecules with a
heteroconjugated system. This study could aid the devel-
opment of methods for quantifying epoxidation and
hydroxylation of coumarin derivatives, and contribute to
understanding antioxidant activity of coumarins, a bio-
logical property currently considered as a promising
approach for the treatment of different diseases.
Figure 3. Simulated EPR spectra of the reaction mixture (4-methyl-
coumarin derivative and dimethyldioxirane).
In addition, reaction between selected 4-methylcoum-
rins and dimethyldioxirane has been examined by EPR
spectroscopy. Immediately after mixing the degassed
solutions of dimethyldioxirane (0.12 mol/L) and 4-meth-
ylcoumarin (0.01 mol/L) in acetone, the solution of
spin-trap compound was added, and EPR spectra were
recorded. The same experiments were repeated after a
particular time period (30, 60, and 120 min). During the
course of the study, DEPMPO has been chosen as a
spin-trap compound. The hyperfine splitting constants of
radical adducts were calculated from simulations of ex-
perimental. Presented spectra (Fig. 3) show that reaction
mixture contained three radical adducts, hydroxy radical,
O-centered radical, and C-centered radical, in different
portions which rate was changing during the reaction.
The hyperfine splitting constants for OH radical (after
EXPERIMENTAL SECTION
General. All reagents were purchased from Sigma-Aldrich,
Fluka, and Kemika Chemical Company. Synthesized 4-methyl-
coumarins were identified by determination of melting points
on Kofler microscope hot stage apparatus, using elemental
analysis on CHN Analyzer, GC/MS and NMR techniques.
The GC conditions were as follows: the fused-silica HP-5
column (5% phenyl methyl siloxane; 30 m ꢁ 250 lm ꢁ 0.25
lm), carriers gas He (1.1 mL/min), temperature program:
20ꢂC/min from 100 to 270ꢂC; the injection port temperature
was 250ꢂC; detector temperature 280ꢂC. Ionization of the sam-
ple components was performed in the EI mode, (70 eV). The
NMR spectra were recorded in CDCl3, acetone-d6 and DMSO-
d6 at 300 MHz using Bruker DPX 300 NMR spectrometer.
The EPR spectra of the reaction were measured with a Bruker
ELEXSYS E500 spectrometer (X band, 9.33 GHz) at room
temperature (ꢃ20ꢂC). The operating conditions were as fol-
lows: microwave power 20.06 mW, center field 332.67 mT,
sweep width 16.0 mT, modulation frequency 100 kHz, modu-
lation amplitude 0.1 mT, gain 60 dB, time constant 1.28 ms. A
computer simulation of the hyperfine coupling constants was
carried out using the WIN-EPR software package (Bruker,
USA) and EPRISM-C Wizard 6.2 software.
30 min) were aP ¼ 4.73 mT, aH ¼ 1.10 mT, and aN
¼
1.32 mT, for O-centered radical adduct were aP ¼ 4.66
mT, aH ¼ 0.79 mT, and aN ¼ 1.27 mT, and for C-cen-
tered radical adduct were aP ¼ 4.80 mT, aH ¼ 1.95 mT,
and aN ¼ 1.39 mT. These results are comparable with
those found in literature [23–25]. However, a portion of
hydroxyl and C-centered radical adduct increased during
the reaction, whereas a portion of O-radical adduct
decreased. The presence of hydroxyl radical can be
explained by reaction of the proton of the hydroxy
group attached at aromatic part of coumarin molecule.
Resulting phenoxyl radical of coumarin substrate can be
stabilized by resonance [6]. In addition, the presence of
General procedure for the preparation of 4-methlycou-
marin hydroxy and epoxy derivatives. A flask containing
2.5-mL dimethyldioxirane solution (0.12 mol/L) and 0.5 mL
solution of 4-methylcoumarin (0.01 mol/L) was carried at
room temperature, in dry acetone solution, in the absence of
sunlight and air. The progress of reaction was monitored by
GC/MS. The yields of reaction products are calculated using
semi-quantitative analysis carried out directly from peak areas
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Oxidative Transformations of 4-Methylcoumarins Using Dimethyldioxirane
265
in the GC profile. At the end of the reaction, products were
determined with different 1D and 2D NMR techniques. In
addition, an experiment under inert atmosphere (argon) was
carried out to confirm that obtained products are direct oxida-
tion products.
Reaction kinetics. Kinetic studies of reaction between dime-
thyldioxirane (12 equiv) and 4-methylcoumarins were carried at
various temperatures in a thermostated cell (20, 25, 30, and
40ꢂC), using UV–vis spectrophotometric method, for 2–5 h. Data
for kinetic analyses were collected using Varian Cary 50 Bio
UV–vis spectrophotometer. UV–vis spectra were recorded at
wavelength range from 300 to 800 nm, using Xenon lamp. All
kinetics experiments were carried out in triplicate.
3-Hydroxy-4-methyl-2H-chromen-2-one (2a). Yield 59.4%.
1H-NMR (300.13 MHz, DMSO-d6) d 7.57–7.18 (m, 4H,
ArAH), 5.37 (s, 1H, 3-OH), 2.34 (s, 3H, 4-CH3). MS (EI, 70
eV): m/z (%) ¼ 65 (11), 77 (9), 91 (35), 120 (23), 147 (37),
176 [M]þ (100).
3,4-Dihydro-4-methyl-2H-oxireno[c]chromen-2-one (3a). Yield
39.5%. 1H-NMR (300.13 MHz, DMSO-d6) d 7.55–7.21 (m,
4H, ArAH), 3.83 (s, 1H, 3-H), 2.38 (s, 3H, 4-CH3). MS (EI,
70 eV): m/z (%) ¼ 43 (11), 51 (18), 65 (24), 77 (22), 91 (99),
105 (43), 120 (18), 132 (100), 147 (14), 176 [M]þ (41).
(%) ¼ 51 (33), 65 (15), 77 (34), 91 (56), 105 (32), 117 (34),
133 (33), 146 (100), 162 (21), 174 (42), 190 [M]þ (79).
3-Hydroxy-6-methoxy-4-methyl-2H-chromen-2-one (2e). Yield
1
54.8%. H-NMR (300.13 MHz, DMSO-d6 d 7.32 (d, J1 ¼ 8.3
Hz, 1H, 5-H), 7.21 (d, J2 ¼ 3.2 Hz, 1H, 8-H), 7.06 (dd, J1 ¼
8.3 Hz, J2 ¼ 3.2 Hz, 1H, 7-H), 5.32 (s, 1H, 3-OH), 3.84 (s,
3H, 6-OCH3), 2.43 (s, 3H, 4-CH3). MS (EI, 70 eV): m/z (%)
¼ 77 (16), 91 (7), 135 (34), 150 (20), 178 (10), 191 (10), 206
[M]þ (100).
3,4-Dihydro-6-methoxy-4-methyl-2H-oxireno[c]chromen-
2-one (3e). Yield 29.3%. 1H-NMR (300.13 MHz, DMSO-d6)
d 7.11 (d, J1 ¼ 8.5 Hz, 1H, 5-H), 7.04 (d, J2 ¼ 3.0 Hz, 1H, 8-
H), 6.96 (dd, J1 ¼ 8.5 Hz, J2 ¼ 3.0 Hz, 1H, 7-H), 3.88 (s, 1H,
3-H), 3.84 (s, 3H, 6-OCH3), 2.32 (s, 3H, 4-CH3). MS (EI, 70
eV): m/z (%) ¼ 51 (21), 57 (39), 65 (27), 69 (30), 77 (38), 85
(18), 91 (51), 97 (22), 107 (25), 111 (15), 119 (26), 135 (67),
147 (66), 162 (100), 178 (10), 190 (77), 206 [M]þ (79).
3-Hydroxy-7-methoxy-4-methyl-2H-chromen-2-one (2f). Yield
1
23.1%. H-NMR (300.13 MHz, DMSO-d6) d 7.94 (d, J2 ¼ 2.1
Hz, 1H, 5-H), 7.12 (dd, J1 ¼ 8.2 Hz, J2 ¼ 2.1 Hz, 1H, 6-H),
7.03 (d, J1 ¼ 8.2 Hz, 1H, 8-H), 4.96 (s, 1H, 3-OH), 3.82 (s,
3H, 7-OCH3), 2.26 (s, 3H, 4-CH3). MS (EI, 70 eV): m/z (%)
¼ 44 (18), 69 (13), 77 (13), 89 (12), 135 (10), 163 (55), 191
(19), 206 [M]þ (100).
3-Hydroxy-4,6-dimethyl-2H-chromen-2-one
(2b). Yield
83.2%. 1H-NMR (300.13 MHz, DMSO-d6) d 7.40 (d, J1
¼
3,6-Dihydroxy-4-methyl-2H-chromen-2-one
(2g). Yield
7.2, 1H, 5-H), 7.21 (d, J2 ¼ 2.7 Hz, 1H, 8-H), 7.12 (dd, J1
¼7.2 Hz, J2 ¼2.7 Hz, 1H, 7-H), 5.29 (s, 1H, 3-OH), 2.41 (s,
3H, 4-CH3), 2.12 (s, 3H, 6-CH3). MS (EI, 70 eV): m/z (%) ¼
51 (10), 77 (14), 91 (20), 105 (10), 115 (12), 132 (21), 161
(32), 190 [M]þ (100).
28.4%. 1H-NMR (300.13 MHz, DMSO-d6) d 9.76 (s, 1H, 6-
OH), 7.19 (d, J1 ¼ 7.8 Hz, 1H, 5-H), 7.11 (d, J2 ¼ 2.9 Hz,
1H, 8-H), 6.83 (d, J1 ¼ 7.8 Hz, J2 ¼ 2.9 Hz, 1H, 7-H), 4.47
(s, 1H, 3-OH), 2.29 (s, 3H, 4-CH3). MS (EI, 70 eV): m/z (%)
¼ 43 (10), 53 (13), 107 (10), 121 (36), 137 (34), 163 (32),
192 [M]þ (100).
3,4-Dihydro-4,6-dimethyl-2H-oxireno[c]chromen-2-one
1
(3b). Yield 13.8%. H-NMR (300.13 MHz, DMSO-d6) d 7.62
3,4-Dihydro-6-hydroxy-4-methyl-2H-oxireno[c]chromen-
2-one (3g). Yield 62.8%. 1H-NMR (300.13 MHz, DMSO-d6)
d 9.81 (s, 1H, 6-OH), 7.20 (d, J1 ¼ 8.0 Hz, 1H, 5-H), 7.15 (d,
J2 ¼ 2.8 Hz, 1H, 8-H), 6.88 (dd, J1 ¼8.0 Hz, J2 ¼ 2.8 Hz,
1H, 7-H), 3.73 (s, 1H, 3-H), 2.32 (s, 3H, 4-CH3). MS (EI, 70
eV): m/z (%) ¼ 55 (12), 80 (10), 107 (13), 121 (22), 136 (50),
148 (17), 163 (18), 176 (100), 192 [M]þ (62).
(d, J2 ¼ 2.3 Hz, 1H, 5-H),7.30 (dd, J1 ¼ 7.6 Hz, J2 ¼ 2.3 Hz,
1H, 7-H), 7.13 (d, J1 ¼ 7.6 Hz, 1H, 8-H), 5.41 (s, 1H, 3-H),
2.46 (s, 3H, 4-CH3), 2.03 (s, 3H, 6-CH3). MS (EI, 70 eV): m/z
(%) ¼ 51 (37), 65 (23), 77 (38), 91 (67), 103 (39), 117 (44),
132 (26), 139 (2), 146 (100), 161 (22), 174 (24), 190 [M]þ
(39).
3-(D)Hydroxy-4,6-dimethyl-2H-chromen-2-one (2c). Yield
3,7-Dihydroxy-4-methyl-2H-chromen-2-one
(2h). Yield
1
43.1%. H-NMR (300.13 MHz, DMSO-d6) d 7.41 (d, J1¼ 7.6
49.3%. 1H-NMR (300.13 MHz, DMSO-d6) d 9.22 (s, 1H, 7-
OH), 7.64 (d, J2 ¼ 2.8 Hz, 1H, 5-H), 7.11 (dd, J1 ¼ 8.0 Hz,
J2 ¼ 2.8 Hz, 1H, 6-H), 7.01 (d, J1 ¼ 8.0 Hz, 1H, 8-H), 4.74
(s, 1H, 3-OH), 2.09 (s, 3H, 4-CH3). MS (EI, 70 eV): m/z (%)
¼ 53 (10), 69 (10), 77 (10), 107 (10), 121 (13), 136 (23), 147
(10), 164 (32), 192 [M]þ (100).
Hz, 1H, 5-H), 7.13 (d, J2 ¼ 2.9 Hz, 1H, 8-H), 6.98 (dd, J1 ¼
7.6 Hz, J2 ¼ 2.9 Hz, 1H, 7-H), 2.31 (s, 3H, 4-CH3), 2.19 (s,
3H, 6-CH3). MS (EI, 70 eV): m/z (%) ¼ 51 (13), 53 (15), 77
(19), 133 (48), 162 (34), 191 [M]þ (100).
3,4-(3D)Dihydro-4,6-dimethyl-2H-oxireno[c]chromen-2-one
(3c). Yield 11.5%. 1H-NMR (300.13 MHz, DMSO-d6 d 7.17 (d,
J1 ¼ 7.9 Hz, 1H, 5-H), 7.10 (d, J2 ¼ 3.1 Hz, 1H, 8-H), 7.03 (dd,
J1 ¼ 7.9 Hz, J2 ¼ 3.1 Hz, 1H, 7-H), 2.30 (s, 3H, 4-CH3), 2.16 (s,
3H, 6-CH3). MS (EI, 70 eV): m/z (%) ¼ 51 (41), 78 (56), 92
(46), 133 (100), 147 (100), 162 (43), 191 [M]þ (27).
3,7-Dihydroxy-4,8-dimethyl-2H-chromen-2-one (2i). Yield
34.9%. 1H-NMR (300.13 MHz, DMSO-d6) d 9.48 (s, 1H, 7-
OH), 7.24 (d, J1 ¼ 2.2 Hz, 1H, 5-H), 6.91 (d, J1 ¼ 2.2 Hz,
1H, 6-H), 4.92 (s, 1H, 3-OH), 2.43 (s, 3H, 4-CH3), 2.31 (s,
3H, 8-CH3). MS (EI, 70 eV): m/z (%) ¼ 77 (17), 83 (3), 107
(10), 135 (19), 150 (19), 178 (28), 206 [M]þ (100).
3-Hydroxy-4,7-dimethyl-2H-chromen-2-one
(2d). Yield
1
47.5%. H-NMR (300.13 MHz, DMSO-d6) d 7.62 (d, J2 ¼ 2.3
Hz, 1H, 5-H), 7.30 (dd, J1 ¼ 7.6 Hz, J2 ¼ 2.3 Hz, 1H, 6-H),
7.13 (d, J1 ¼ 7.6 Hz, 1H, 8-H), 5.41 (s, 1H, 3-OH), 2.28 (s,
3H, 4-CH3), 2.03 (s, 3H, 7-CH3). MS (EI, 70 eV): m/z (%) ¼
(13), 91 (15), 105 (10), 134 (21), 161 (26), 190 [M]þ (100).
3,4-Dihydro-4,7-dimethyl-2H-oxireno[c]chromen-2-one
3,6-Dihydroxy-4,7-dimethyl-2H-chromen-2-one (2j). Yield
45.7%. 1H-NMR (300.13 MHz, DMSO-d6) d 9.64 (s, 1H, 6-
OH), 7.26 (s, 1H, 5-H), 7.04 (s, 1H, 8-H), 4.86 (s, 1H, 3-OH,
2.39 (s, 3H, 4-CH3), 2.23 (s, 3H, 7-CH3). MS (EI, 70 eV): m/z
(%) ¼ 51 (10), 77 (19), 107 (12), 135 (27), 150 (21), 163
(11), 178 (32), 206 [M]þ (100).
3,4-Dihydro-6-hydroxy-4,7-dimethyl-2H-oxireno[c]chro-
men-2-one (3j). Yield 62.8%. 1H-NMR (300.13 MHz,
DMSO-d6) d 9.56 (s, 1H, 6-OH), 7.21 (s, 1H, 5-H), 7.07 (s,
1H, 8-H), 3.79 (s, 1H, 3-H), 2.31 (s, 3H, 4-CH3), 2.19 (s, 3H,
1
(3d). Yield 42.2%. H-NMR (300.13 MHz, DMSO-d6) d 7.19
(d, J2 ¼ 2.8 Hz, 1H, 5-H), 7.12 (d, J1 ¼ 7.7 Hz, J2 ¼ 2.8 Hz,
1H, 6-H), 6.88 (d, J1 ¼ 7.7 Hz, 1H, 8-H), 3.82 (s, 1H, 3-H),
2.38 (s, 3H, 4-CH3), 2.11 (s, 3H, 7-CH3). MS (EI, 70 eV): m/z
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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S. Cavar and F. Kovac
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Vol 49
[10] Takeda, S.; Aburada, M. J Pharmacobiodyn 1981, 6, 724.
7-CH3). MS (EI, 70 eV): m/z (%) ¼ 51 (15), 65 (12), 69 (10),
77 (23), 91 (15), 103 (12), 107 (12), 115 (11), 133 (13), 150
(15), 162 (100), 178 (22), 190 (79), 206 [M]þ (73).
[11] Deana, A. A.; Stokker, G. E.; Schultz, E. M.; Smith, L. R.;
Cragoe, E. J., Jr.; Russo, H. F.; Watson, L. S. J Med Chem 1983, 26,
580.
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[12] Cavar, S.; Kovac, F. Int J Chem Kinet 2009, 41, 414.
ˇ
Acknowledgments. We are gratefully acknowledged to the Lab-
[13] Woodruff, E. H. Org Synth 1955, 3, 581.
ˇ
ˇ
oratory of biophysics—EPR centre Ljubljana, ‘‘Jozef Stefan’’
Institute for providing the EPR spectra, and to our contract grant
sponsor: Ministry of Higher Education, Science and Technology,
the Republic of Slovenia.
[14] Vogel, A. I.; Tatchell, A. R.; Furnis, B. S.; Hannaford, A.
J.; Smith, P. W. G. Vogel’s Textbook of Practical Organic Chemistry,
5th ed.; Prentice Hall: London, England, 1996; pp 1190–1193.
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[15] Cavar, S. Academic Dissertation. University of Ljubljana,
Faculty of Chemistry and Chemical Technology: Slovenia, 2010.
[16] Murray, R. W.; Shiang, D. L. J Chem Soc Perkin Trans 2
1990, 2, 349.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet