Synthesis of 6- and 7-alkoxy-4-methylcoumarins from corresponding hydroxy coumarins and their conversion into 6- and 7-alkoxy-4-formylcoumarin derivatives

Article abstract of DOI:10.1080/00397911.2020.1807571

Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared from hydroquinone and resorcinol through their reaction with ethyl acetoacetate. These hydroxy coumarins were then converted into corresponding alkoxy derivatives by reaction with alkyl halides. The yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55?95%. Oxidation of these compounds by selenium dioxide under conventional and microwave-assisted heating conditions produced corresponding 4-formyl compounds 5b–h and 6b–h with yields of 40?67% and 90?93%, respectively. Several 6- and 7-alkoxy-4-methylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h are novel compounds.

Full text of DOI:10.1080/00397911.2020.1807571

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of 6- and 7-alkoxy-4-methylcoumarins
from corresponding hydroxy coumarins and their
conversion into 6- and 7-alkoxy-4-formylcoumarin
derivatives
Vu Ngoc Toan & Nguyen Dinh Thanh
To cite this article: Vu Ngoc Toan & Nguyen Dinh Thanh (2020): Synthesis of 6- and 7-
alkoxy-4-methylcoumarins from corresponding hydroxy coumarins and their conversion
into 6- and 7-alkoxy-4-formylcoumarin derivatives, Synthetic Communications, DOI:
10.1080/00397911.2020.1807571
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1807571
Synthesis of 6- and 7-alkoxy-4-methylcoumarins from
corresponding hydroxy coumarins and their conversion
into 6- and 7-alkoxy-4-formylcoumarin derivatives
Vu Ngoc Toana,b
and Nguyen Dinh Thanhb
aInstitute for Chemistry and Materials, Vietnam Academy of Military Science and Technology, Hanoi,
b
Vietnam; Faculty of Chemistry, VNU University of Science (Vietnam National University),
Hanoi, Vietnam
ABSTRACT
ARTICLE HISTORY
Received 20 July 2020
Hydroxy derivatives of 4-methyl-2H-chromen-2-one were prepared
from hydroquinone and resorcinol through their reaction with ethyl
acetoacetate. These hydroxy coumarins were then converted into
corresponding alkoxy derivatives by reaction with alkyl halides. The
yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were
55ꢀ95%. Oxidation of these compounds by selenium dioxide under
conventional and microwave-assisted heating conditions produced
corresponding 4-formyl compounds 5b–h and 6b–h with yields of
40ꢀ67% and 90ꢀ93%, respectively. Several 6- and 7-alkoxy-4-meth-
ylcoumarins 3a–i, 4a–i and nearly all 6- and 7-alkoxy-4-formylcou-
marins 5b–h, 6b–h are novel compounds.
KEYWORDS
4-Formylcoumarin; 4-
methylcoumarin; micro-
wave-assisted; Riley’s
oxidation; Williamson
ether synthesis
GRAPHICAL ABSTRACT
Introduction
Derivatives of coumarin (2H-chromen-2-one) found in many applications as fragrances,
pharmaceuticals and agrochemicals. Some 4-methylcoumarin derivatives were also use-
ful as anticancer,[1] inflammatory,[2] antioxidant,[3,4] and cytotoxic[4] agents. The func-
tionalization of coumarin ring by formyl group facilitated the synthesis of various
compounds that carry this ring based on the properties of the formyl group, such as
thiosemicarbazones,[5,6] coumarin-substituted benzothiazole derivatives,[7] coumarin
Schiff bases,[8] etc. Their 7-methoxy- and 7-ethoxy derivatives remained as the most
selective inhibitors for the coumarin 7-hydroxylase (Coh) enzyme.[9] Literatures have
described several pathways for the synthesis of alkoxy coumarins by Pechmann
CONTACT Nguyen Dinh Thanh
nguyendinhthanh@hus.edu.vn
Faculty of Chemistry, VNU University of Science
(Vietnam National University), 19 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
V. NGOC TOAN AND N. DINH THANH
reaction[10] of substituted phenols with donated electron and methyl or ethyl acetoace-
tate in the presence of protonic acid (conc. H2SO4),[11] Lewis acids (boron trifluoride
[15]
dihydrate,[12] AlCl3, ZnCl2,[10,13] ZnCl2/Al2O3,[14] ZrCl4
etc.), zirconyl chloride octa-
hydrate,[16] dehydrating agents (P2O5) or montmorillonite clay,[17] and ionic liquids,
such as phosphorus oxychloride in 1-butyl-3-methyl-imidazolium chloride ([bmim]Cl),
1-butyl-3-methylimidazolium bromide ([bmim]Br), and 1-butyl-3-methylimidazolium
tetrafluoroborate ([bmim]BF4), phosphoric acid and imidazolium dihydrogen phos-
phate,[18] [bmim]Cl.2AlCl3,[19] (and lastly) SelectfluorTM [1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoro-borate)].[20] There were also literatures
regarding the synthesis of the alkoxy coumarins through Williamson ether synthesis.
Several known alkoxy 4-methylcoumarins were prepared by Pechmann of different
alkoxy phenols, such as 6-methoxy-4-methylcoumarin from 3-methoxyphenol,[16] 6-
ethoxy-4-methylcoumarin from 6-ethoxyphenol,[4] 7-methoxy-4-methylcoumarin from
3-methoxyphenol,[19] and 7-ethoxy-4-methylcoumarin from 3-ethoxyphenol.[20]
It is well known that the formyl group could be introduced on benzene moiety when
coumarins bearing the hydroxy group on this aromatic ring (so-called hydroxycoumar-
ins) by reaction with hexamethylenetetramine in hot acetic acid (Sommelet reaction)[21]
or on 2H-pyran-2-one moiety in positions 3 or 4. A series of substituted 3-formylcou-
marins were prepared from 3-cyanocoumarinsby reduction of 3-cyanocoumarins with
Raney nickel in formic acid.[22] Other preparation methods for these aldehydes included
reaction of trimethylsilyl propiolate esters of salicylaldehydes with DABCO in THF,[23]
dibromination of 3-methylcoumarin with subsequent hydrolysis in AcONa/AcOH (for
preparation of 7-butoxy-3-formylcoumarin),[24,25] Rosenmund reduction of some cou-
marin-3-carbonyl chlorides,[26] or through unusual rearrangement of 2-morpholino-3-
cyanochromenes.[27] 7-Dialkyl- and diarylaminocoumarins could also react with
Vilsmeier reagent to give 3-formyl derivatives.[28] 3-Methylcoumarin and its 6-chloro-
and 6-bromo-substituted derivatives can be converted into corresponding 3-carbalde-
hydes by selenium dioxide oxidation under microwave-assisted conditions.[29]
4-Methyl coumarins could be converted into 4-formylcoumarins using different
oxidizing agents with good yields.[30–32] Holiyachi et al.[33] reported that substituted 4-
formylcoumarins could be prepared from corresponding 4-bromomethylcoumarins by
using excesses DMSO in presence of base (TEA/Na2CO3) under heating conditions
(Kornblum’s oxidation).[34,35] In this protocol, some substituted 4-formylcoumarins
were synthesized with different substituents on benzene ring, including 6- or 7-methyl,
6-methoxy, 7-hydroxy, 5,7-dimethyl, 6-chloro, and 6-bromo groups, with yields of
84ꢀ91% and solvent DMSO did not be recycled.[33] Lin et al. examined the two-step
synthetic path for substituted 4-formylcoumarins[36] by hydrolysis of corresponding 7-
methyl- and 7-hydroxy-4-chloromethylcoumarins and subsequent oxidation of the
obtained coumarin alcohols with manganese dioxide as oxidant under reflux in THF. In
Lin’s protocol, 4-methyl group on coumarin ring should be converted into 4-chloro-
methyl first. Methyl group in methyl arenes and methyl heteroarenes could be oxidized
directly into formyl one by using the selenium dioxide-mediated oxidation (Riley’s oxi-
dation).[37,38] Razzak Mahmood Kubba et al. also obtained 4-formyl-7-hydroxycoumarin
with yield of 35% by SeO2-oxidation of 7-hydroxy-4-methylcoumarin.[39] Ito and Kaoru
used selenium dioxide in xylene as the specific oxidizing agent in cases of 7-substituted

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3
4-methylcoumarins (with substituents being H, Me, NEt2, Ac, OH) for 8 h under reflux
in yields of 27ꢀ75%.[30,32] Tanakao et al. prepared 4-formyl-7-methoxycoumarin with
yield of 26% by using SeO2-oxidation in dry chlorobenzene for 20 h.[40] Gonc¸alves et al.
converted 6-methoxy-4-methyl-2-oxo-2H-benzo[h]benzopyran into 4-formyl derivative
(with yield of 79%) by heating the compound with selenium dioxide in chlorobenzene
under reflux for until 36 h.[41] El Azab et al. prepared 4-formyl-6-hydroxycoumarin
from corresponding 6-hydroxy-4-methylcoumarin using SeO2 in DMF in the presence
of glacial AcOH (with catalytic amount)[42] by using conventional and microwave-
assisted heating methods with yields of 85 and 97%, respectively. Wang et al. performed
the SeO2-oxidation of 6,7-dimethoxy-4-methylcoumarin in xylene to produce corre-
sponding 4-formyl coumarin with yield of 91%.[43] Buechi et al. synthesized 5-benzy-
loxy-7-methoxy- and 5,7-dibenzyloxy-4-formylcoumarins in yields of 93% from
corresponding 4-methyl derivatives using resublimed selenium dioxide in xylene for
6 hrs. Gabr prepared three 4-formyl coumarin derivatives including 6,8-dichloro-, 6,8-
dimethoxy-7-methyl and 7-amino-4-formylcoumarins with yields of 72, 87, and 51%,
respectively, from corresponding 4-methyl derivatives by SeO2-oxidation in xylene for
24 h.[44] Bray et al. prepared 6-(tert-butyldimethylsilyloxy)-4-formyl-7-methylcoumarin
with yield of 78% by heating 4-methyl derivative and SeO2 in xylenes at 100 ꢁC.[45]
Moorthy et al. synthesized 6- and 7-fluoro-, 6- and 7-chloro-, 7-bromo- and unsubsti-
tuted 4-formylcoumarins with yields of 58ꢀ87% by melting corresponding 4-methylcou-
marins with SeO2 at 160ꢀ170 ꢁC for 1 h.[46] Until now there has been no publication
for the synthesis of 4-formylcoumarins having alkoxy groups on benzene ring directly
from corresponding alkoxy 4-methylcoumarins, except report from Wu F. and cow-
orkers.[47] In their article, the synthesis of several substituted 4-formylcoumarin (with 7-
methyl and 7-methoxy groups) were described but the complete physical and spectral
data for the synthesized aldehydes were not included. Thus, in this article, we have
reported the synthesis of some 6- or 7-alkoxy-4-methylcoumarins and their oxidation
into corresponding 4-formylcoumarins by using activated SeO2 under conventional and
microwave-assisted heating methods. We hoped that these synthesized substituted 4-for-
myl coumarins will be important initial materials for further studies in the synthesis of
compounds with coumarin ring. The synthesis of substituted 4-formylcoumarins created
the opportunity to functionalize the coumarin ring and facilitate the transform associ-
ated with this heterocycle.
Results and discussions
We have provided the synthetic pathway of alkoxy 4-formylcoumarins derived from 6-
and 7-hydroxy-4-methylcoumarins (Scheme 1). Hydroxycoumarins were easily obtained
from corresponding dihydroxy benzene (hydroquinone and resorcinol); the former was
transformed into ether using Williamson ether synthesis, followed by an oxidation
reaction using selenium dioxide as an oxidant. 6-Hydroxy-4-methylcoumarin (2a) and
7-hydroxy-4-methylcoumarin (2b) needed for this study were prepared from hydroquin-
one (1a) or resorcinol (1b), respectively, by Pechmann reaction with ethyl acetoacetate
in the presence of concentrated sulfuric acid as catalyst according to Russell’s proced-
ure.[11] Next, these 6- and 7-hydroxy-4-methylcoumarins (2a and 2b) would be

4
V. NGOC TOAN AND N. DINH THANH
Scheme 1. Synthetic path for 6- and 7-alkoxy-4-methylcoumarins from corresponding 6- or 7-hydrox-
ycoumarins. Reaction conditions: (i) 1. Ethyl acetoacetate, 85% H2SO4, 10–25 ꢁC, 24 h; 2. 5% NaOH
solution, then 20% H2SO4 solution;[11] (ii) see Tables 1 and 2.
converted into corresponding various 6- or 7-alkoxy-4-methylcoumarins (3a–i, 4a–i) by
bimolecular nucleophilic substitution reaction of corresponding hydroxy-4-methylcou-
marins with appropriate alkyl iodides or bromides (Williamson0s ether synthesis).
First, we have examined the influences of the bases and solvents on the reaction times
and the yield of the ether products. Reaction of 6-hydroxy-4-methylcoumarin with
methyl iodide was chosen as the model reaction (Table 1). The bases used in
Williamson ether synthesis of phenols (in this research they were 6- and 7-hydroxy-4-
methylcoumarins) could be potassium carbonate, sodium carbonate, sodium hydroxide,
and sodium hydride.[48–50] It is known that coumarin ring readily opened in the pres-
ence of strong bases (also strong nucleophiles), such as NaOH,[51] NaOEt (in abs. etha-
nol, under reflux),[52] NaH (in THF at ꢀ30 ꢂ ꢀ40 ꢁC),[53] or NaH in THF in the
presence of methyl iodide at room temperature or under reflux.[54] Thus, these bases
were not used in our research, and only K2CO3 and Na2CO3 were chosen as base in
examining the above-mentioned model reaction. We conducted preliminary investiga-
tions of the influences of sodium and potassium carbonates as basic catalyst and acetone
as solvent on the yield of ether 3a. We found that the use of Na2CO3 instead K2CO3
caused yield of 3a to decrease (yield of 70% with Na2CO3 v.s. yield of 87% with K2CO3
for 6 h under reflux). The lower yield could be due to the lower basicity of the Na2CO3
in comparison with K2CO3.[55]
The solvents used for these investigations were dried solvents, such as acetone, aceto-
nitrile, DMF, and DMSO. The influence of these solvents on the yield of 6-methoxy-4-
methylcoumarin 2a were evaluated. In these processes, anhydrous potassium carbonate
was used to promote Williamson ether reaction. The obtained results were listed in
Table 1.
The results in Table 1 showed that the use of acetone as a solvent was more appro-
priate for this reaction, resulting in higher yields of 3a (87 and 90 for 6 and 12 h under
reflux, Entries 1 and 2, respectively), whereas acetonitrile (Entries 4 and 5) gave lower
yields of 3a (84 and 85% for 6 and 12 h, respectively) depending on the reaction time.
The remaining solvents, DMF (Entries 6, 7, and 8), and DMSO (Entries 9,10) also gave

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5
Table 1. Optimization of solvent conditions for the synthesis of methoxy ether of 6-hydroxy-4-meth-
ylcoumarin (3a).
Entry
Solventsa
Acetone
Acetone
Acetone
Acetonitrile
Acetonitrile
DMF
DMF
DMF
DMSO
DMSO
Reaction time (h)b
Reaction temp. (ꢁC)c
Yield of 6a (%)d
1
2
3
4
5
6
7
8
6
16
24
6
12
6
12
24
6
56
56
56
82
82
100
100
100
100
100
87
90
92
84
85
66
69
64
57
56
9
10
12
aVolumes of reaction solvents: Acetone, 20 mL, Acetonitrile, 20 mL, DMF, 15 mL, DMSO, 15 mL;
bReaction was monitored based on the disappearance of 2a by TLC (toluene/ethyl acetate ¼ 1:2 by volume);
cAt boiling point of reaction solvent, except DMF, DMSO: reaction temperature was 70 ꢁC;
dIsolated yields.
The bold values mean the optimal reaction conditions in this synthetic study.
lower yields. DMF and DMSO gave lower yields relative to the solubility of the products
and were difficult to handle. The removal of DMF or DMSO from reaction mixture was
difficult even at reduced pressure, and on a workup of reaction mixtures, most of the
product was lost with DMF-water or DMSO-water mixtures. The product yields in these
cases were about 64ꢀ69% and 56ꢀ57%, respectively. Conversely, the use of dried acet-
one or acetonitrile as the solvent for this reaction held several advantages, and both sol-
vents gave remarkable and similar yields (Entries 1ꢀ5). Acetone could easily be
removed from the reaction mixture in vacuum due to its low boiling point, and its
removal would not affect product yields, even with temperature-sensitive products
(ethers 3i and 4i, for reactions of allyl bromide with 2a in Entries 8 and 18, respectively,
in Table 2). Extending the reaction time (from 24 h to 36 h, Entries 1ꢀ3) increased the
yields unremarkably, 90 vs. 92% (Entries 2 and 3).[55]
Therefore, the optimal reaction conditions were dried acetone as a solvent, anhydrous
K2CO3 as a base, and the reaction time of 24 hours at a temperature of 56 ꢁC. These
conditions were used in the synthesis of other ethers 3b–i and 4a–i. In case of alkyl
chloride or alkyl bromide, a small amount of KI (1 mol%) was supplemented to the
reaction mixture in order to promote the SN2 process. The obtained results were listed
in Table 2. Yields of 6- and 7-alkoxy-4-methylcoumarins 3a–i and 4a–i were 55ꢀ95%.
Almost all obtained 6- and 7-alkoxycoumarins in this study are novel compounds,
and their structures were confirmed by spectroscopic methods. IR spectra of com-
pounds 3a–i and 4a–i displayed characteristic absorption bands at 1737ꢀ1708 cmꢀ1
(C¼O lactone), 1293ꢀ1242 cmꢀ1 and 1170ꢀ1142 cmꢀ1 (CꢀOꢀC group in lactone
and ether functional groups). 1H NMR showed chemical shifts at 7.66ꢀ6.17 ppm
(coumarin protons) and 4.03ꢀ0.88 ppm (protons in the alkoxy group). Methylene
group attached to oxygen atom had signal at about 4.07ꢀ4.00 ppm. 13C NMR

6
V. NGOC TOAN AND N. DINH THANH
Table 2. Synthesis of 6-alkoxy- and 7-alkoxy-4-methylcoumarins (3a–i, 4a–i).
Entry
R
Reaction time (h)a,b
Yield (%)c
1
2
3
4
5
6
7
8
6-Methoxy
6-Ethoxy
6-Propoxy
6-Isopropoxy
6-Butoxy
6-Isobutoxy
6-Pentoxy
6-Isopentoxy
6-Allyloxy
7-Methoxy
7-Ethoxy
7-Propoxy
7-Isopropoxy
7-Butoxy
3a
3b
3c
3d
3e
3f
3g
3h
3i
4a
4b
4c
4d
4e
4f
4g
4h
4i
16
16
16
16
12
12
12
12
12
18
18
15
15
12
12
12
12
12
92
85
75
60
85
75
84
79
85
90
85
70
75
55
57
95
82
87
9
10
11
12
13
14
15
16
17
18
7-Isobutoxy
7-Pentoxy
7-Isopentoxy
7-Allyloxy
a
Note: Reaction conditions: RꢀCl, RꢀBr or RꢀI, K2CO3, acetone, under reflux;
bIn cases of chlorides and bromides, KI (1 mol%) was added;
cIsolated yields.
spectra displayed resonance signals of carbon atoms in molecules, for examples, at
160.6ꢀ101.1 ppm (carbon atoms in the coumarin component, except C¼O lactone
atom), 162.2ꢀ159.9 ppm (carbon atom in C¼O lactone group), 30.7ꢀ10.7 ppm (car-
bon atoms in the alkoxy group, except methylene carbon atom attached to oxygen)
depending on their positions in carbon alkyl chain, and 74.3ꢀ64.2 ppm (methylene
carbon atom attached to oxygen).
Methyl group on position 4 of 6- and 7-alkoxy-4-methylcoumarins was converted
into formyl group by oxidation using activated selenium dioxide as selective oxidant.
The solvent used in this oxidation was xylene (Riley’s oxidation)[37] according to modi-
fied literature procedure.[32] It is known that microwave irradiation accelerates the reac-
tions.[56] As such, besides the conventional heating method, in this study we also
performed the SeO2-oxidation reaction under microwave-assisted conditions. The syn-
thetic pathways for 6- and 7-alkoxy-4-formylcoumarins 5b–h and 6b–h were repre-
sented in Scheme 2, including the conventional and microwave-assisted heating
methods. In the former, the reaction mixture was heated under reflux for 24 hours and
the yields of aldehydes 5b–h and 6b–h achieved were 40ꢀ67%. In the latter, the reac-
tion mixture was heated under microwave-assisted heating conditions for 30ꢀ40 min
and the yields of these aldehydes obtained were 90ꢀ93% (Table 3). The reaction time
was dramatically reduced for each substitution from 24 h in conventional heating
method to 30ꢀ45 min under microwave irradiation conditions. Solvent volume was also
reduced from 10 mL in conventional heating method to 2 mL under microwave irradi-
ation conditions. Microwave-assisted reactions were conducted in reaction vessels with
reflux condenser in a microwave reactor. We found that SeO2 oxidation carried out
under microwave-assisted conditions had some advantages over traditional method:
reaction time was shorter (30 vs. 24 hours), product yields were higher (90ꢀ93% vs.
40ꢀ67%), and solvent amounts were smaller (2 vs. 10 mL, less than 5 times.
IR spectra of these aldehyde compounds 5b–h and 6b–h displayed characteristic
absorption bands for functional groups that are present in the molecule.

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7
Scheme 2. Synthetic path for substituted 6-alkoxy- and 7-alkoxycoumarins. Reaction conditions: (i)
activated SeO2, xylene, for 24 h under reflux conditions; (ii) activated SeO2, xylene, under microwave-
assisted reflux conditions for 30ꢀ45 min.
Table 3. Synthesis of 6-alkoxy- and 7-alkoxy-4-formylcoumarins 5b–h, 6b–h.
Conventional heating procedure (Method A) Microwave-assisted heating procedure (Method B)a
Entry
R
Reaction time (h)
Yield (%)b
Reaction time (min)
Yield (%)b
1
2
3
4
5
6
7
8
9
6-Ethoxy
6-Propoxy
5b
5c
24
24
24
24
24
24
24
24
24
24
24
24
24
24
65
67
50
41
40
62
50
60
50b
60
50c
46
40
40
30
30
30
45
45
45
45
30
30
30
45
45
45
45
90
93
92
91
92
90
90
92
91
90
92
92
91
91
6-Isopropoxy 5d
6-Butoxy 5e
6-Isobutoxy 5f
6-Pentoxy 5g
6-Isopentoxy 5h
7-Ethoxy
7-Propoxy
6b
6c
10 7-Isopropoxy 6d
11 7-Butoxy 6e
12 7-Isobutoxy 6f
13 7-Pentoxy 6g
14 7-Isopentoxy 6h
a
Note: At microwave power of 450 W;
bisolated yield.
Intense absorption bands characterized the stretching vibration for these functional
groups, for examples, in region at 1737ꢀ1712 cmꢀ1 (ꢀC¼O lactone), 1710ꢀ1700 cmꢀ1
(ꢀC¼O aldehyde), 1270ꢀ1243 cmꢀ1 and 1151ꢀ1145 cmꢀ1 (ꢀCOC lactone and ether). The
benzene ring of coumarin had some characteristic absorption bands for aromatic C¼C
bonds in region at 1540ꢀ1480 cmꢀ1
.
1H NMR spectra exhibited chemical shifts in
accordance with the structure of compounds 5b–h and 6b–h. Protons of coumarin ring
had chemical shifts in region at d ¼ 8.00ꢀ6.33 ppm with the splitting pattern in agree-
ment with the substitution on benzene ring of coumarins. Proton of the formyl group
gave resonance signal at d ¼ 10.1ꢀ10.2 ppm, while alkyl protons had chemical shifts in
region at d ¼ 1.94ꢀ0.84 ppm. 13C NMR spectra displayed resonance signals of carbon
atoms that are present in the molecule, with the C atoms in the aldehyde group

8
V. NGOC TOAN AND N. DINH THANH
showing a resonance signal of nearly 193.8 ppm, the C atoms within coumarin showing
signal at d ¼ 155ꢀ109 ppm, and the C-alkyl atoms showing signal at d ¼ 20ꢀ10 ppm.
Conclusion
6-Alkoxy- and 7-alkoxy-4-methylcoumarins were readily prepared by Williamson ether
synthesis from corresponding 6- or 7-hydroxy-4-methylcoumarins using acetone as solv-
ent and potassium carbonate as base. The yields of 6- and 7-alkoxy-4-methylcoumarins
3a–i and 4a–i were 55ꢀ95%. The 4-methyl group of these compounds were converted
into 4-formyl functional group by oxidation using activated selenium dioxide as oxidant
under conventional and microwave-assisted heating conditions. The yields of 6- and 7-
alkoxy-4-formylcoumarins 5b–h and 6b–h were 40ꢀ67% and 90ꢀ93%, respectively.
Almost all 6- and 7-alkoxy coumarins 3a–i and 4a–i and 6- and 7-alkoxy-4-formylcou-
marins 5b–h and 6b–h are novel compounds and were characterized by spectral (IR,
NMR and mass) methods.
Experimental
Melting points were determined by open capillary method on STUART SMP3 (BIBBY
STERILIN, UK). The IR spectra were recorded on FT-IR Affinity-1S Spectrometer
(Shimadzu, Japan) in KBr pellet. The 1H and 13C NMR spectra were recorded on
Avance AV500 Spectrometer (Bruker, Germany) at 500 MHz and 125 MHz, respectively,
using DMSO-d6 as solvent and TMS as an internal standard. Chemical shifts, d, are
given in parts per million (ppm), and spin multiplicities are given as s (singlet), br s
(broad singlet), d (doublet), t (triplet), q (quartet) or m (multiplet). Coupling constants,
J, are expressed in hertz (Hz); ESI-mass spectra were recorded on LC-MS LTQ Orbitrap
XL (Thermo Fisher Scientific Inc., USA) or Agilent 6310 Ion Trap (Agilent
Technologies Inc., USA) in methanol/dichloromethane or methanol using ESI method.
The analytical thin-layer chromatography (TLC) was performed on silica gel 60 WF254
aluminum sheets (Merck, Germany) and was visualized with UV light or by iodine
vapor. Chemical reagents in high purity were purchased from the Merck Chemical
Company (in Viet Nam). All materials were of reagent grade for organic synthesis. The
reaction was monitored by thin-layer chromatographic method (solvent system was
toluene/ethyl acetate ¼ 1:2 by volume). 4-Methyl-6-hydroxy-2H-chromen-2-one (2a), 4-
methyl-7-hydroxy-2H-chromen-2-one (2b) were prepared according to literature
[11]
procedure
from hydroquinone (1a) and resorcinol (1b), respectively. Synthetic pro-
cedures and analytical data (IR, H, 13C NMR, ESI-MS, ESI-HRMS, and elemental ana-
lysis) for compounds, 3a–i, 4a–i, 5b–h, and 6b–h can be found via the “Supplementary
Material” of this article’s webpage.
1
General procedure for synthesis of 6-alkoxy- and 7-alkoxy-4-
methylcoumarins (3a–i,4a–i)
To the suspension of 4-methyl-6- or 7-hydroxy-2H-chromen-2-ones (2a or 2b,
0.02 mol), respectively, in dry appropriate solvent (Tables 1 and 2) was added anhydrous

R
SYNTHETIC COMMUNICATIONSV
9
potassium carbonate (0.04 mol, 5.5 g). The mixture was heated under reflux for 10 min
with stirring. Appropriate alkyl bromide or alkyl iodide was added and reaction mixture
continued to heat under reflux for appropriate time (Tables 1 and 2). Solvent was
removed completely under reduced pressure. Water (20 mL) was added to residue in
order to dissolve inorganic salts. The precipitate was filtered, washed with water until
pH 7, crystallized from 96% ethanol to yield the title compounds 3a–i, and 4a–i.
Synthesis of several typical compounds was described below.
4-Methyl-6-ethoxycoumarin (3b)
From 2a (0.02 mol, 3.52 g), ethyl iodide (0.024 mol, 1.93 mL). Yield: 3.47 g (85%) of 3b
as pale-yellow crystals. M.p.: 116ꢀ117.5 ꢁC (from 96% ethanol), ref.:[4] 161–162 ꢁC
(from 96% ethanol). IR (KBr), ꢀ (cmꢀ1) 1715 (ꢀC¼O lactone), 1572, 1485 (ꢀC¼C arene),
1165 &1067 (ꢀCOC lactone); 1H NMR (500 MHz, DMSO-d6, ppm), d (ppm): 7.27
(d, J ¼ 9.0 Hz, 1H, H-8), 7.16 (dd, J ¼ 9.0, 2.5 Hz, 1H, H-7), 7.11 (d, J ¼ 2.5 Hz, 1H, H-
5), 6.34 (s, 1H, H-3), 4.07 (q, J ¼ 7.0 Hz, 2H, 6-OCH2CH3), 2.39 (s, 3H, 4-CH3), 1.35 (t,
J ¼ 7.0 Hz, 3H, 6-OCH2CH3); 13C NMR (125 MHz, DMSO-d6), d (ppm): 160.3 (C¼O
lactone), 155.3 (C-6), 153.4 (C-8a), 147.6 (C-4), 120.5 (C-5), 119.7 (C-7), 117.8 (C-8),
115.1 (C-4a), 109.2 (C-3), 64.2 (6-OCH2CH3), 18.6 (4-CH3), 15.0 (6-OCH2CH3); ESI-
MS: C12H12O3, calc. for M ¼ 204.1 Da, found: m/z 204.2 ([M]þ); ESI/HRMS: calcd. for
M þ H ¼ 205.0865 Da, found: m/z 205.0873 ([M þ H]þ, 100%); Elemental anal. for
C12H12O3, calcd.: C, 70.58; H, 5.92%; found: C, 70.33; H, 5.81%.
General procedure for synthesis of 6- and 7-alkoxy-4-
formylcoumarins (5b–h,6b–h)
Method A. Conventional heating procedure
To the solution of appropriate 6- or 7-alkoxycoumarins (3b–h, 4b–h) (2 mmol) in dry
xylene (10 mL) was added activated selenium dioxide (3 mmol, 333 mg). The mixture
was boiled (at boiling point of solvent) under reflux for 24 h with stirring. The hot reac-
tion mixture was filtered, the filtrate was cooled in ice bath, and the separated product
was filtered, crystallized from toluene to afford the title compounds (5b–h, 6b–h).
Method B. Microwave-assisted heating procedure
To the solution of appropriate 6- or 7-alkoxycoumarins (3b–h, 4b–h) (2 mmol) in dry
xylene (2 mL) was added activated selenium dioxide (3 mmol, 333 mg). The mixture was
heated under microwave-assisted reflux conditions at power of 450 W for 30ꢀ45 min
(Table 3). The hot reaction mixture was filtered, the filtrate was cooled in ice bath, and
the separated product was filtered, crystallized from toluene to afford the title com-
pounds (5b–h, 6b–h).
4-Formyl-6-ethoxycoumarin (5b)
From 3b (2 mmol, 408 mg). Yield: 283 mg (65%, method A), 392 mg (90%, method B)
of 5b as yellow crystals. M.p.: 167ꢀ168 ꢁC (from toluene). IR (KBr), ꢀ cmꢀ1: 1736
(ꢀC¼O lactone), 1708 (ꢀC¼O aldehyde), 1565, 1430 (ꢀC¼C arene), 1243 &1054 (ꢀCOC

10
V. NGOC TOAN AND N. DINH THANH
lactone); 1H NMR (500 MHz, DMSO-d6), d (ppm): 10.15 (s, 4-CHO), 7.96 (d,
J ¼ 3.0 Hz, 1H, H-5), 7.40 (d, J ¼ 9.0 Hz, 1H, H-8), 7.27 (dd, J ¼ 9.5, 3.0 Hz, 1H, H-7),
7.16 (s, H, 1H, H-3), 4.09 (q, J ¼ 7.0 Hz, 2H, 6-OCH2CH3), 1.37 (t, J ¼ 7.0 Hz, 3H, 6-
OCH2CH3); 13C NMR (125 MHz, DMSO-d6), d (ppm): 193.6 (4-CHO), 160.1 (C¼ O
lactone), 155.0 (C-6), 148.2 (C-4), 143.0 (C-8a), 125.3 (C-4a), 119.9 (C-7), 117.3 (C-8),
109.1 (C-3), 63.7 (6-OCH2CH3), 14.5 (6-OCH2CH3); ESI-MS: C12H10O4, calcd. for
M þ H ¼ 219.07 Da, M þ Na ¼ 241.05 Da, found: m/z 219.15 ([M þ H]þ), 241.11
([M þ Na]þ); ESI-MS: calcd. for M þ H ¼ 219.0657 Da, found: m/z 219.0685 ([M þ H]þ,
100%); ESI-HRMS: calcd. for M þ H ¼ 219.0657 Da, found: m/z 219.0661 ([M þ H]þ,
100%); Elemental anal. for C12H10O4, calcd.: C, 69.46; H, 5.30%; found: C, 69.57;
H, 5.41%.
Disclosure statement
No potential conflict of interest was reported by the author(s). Vu Ngoc Toan is principal author,
Nguyen Dinh Thanh is corresponding author.
ORCID
Vu Ngoc Toan
http://orcid.org/0000-0002-4424-7078
Nguyen Dinh Thanh
http://orcid.org/0000-0002-2267-1775
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