Efficient synthesis of 3-methyl-2H-chromen-2-one: Classic versus microwave conditions

Article abstract of DOI:10.1080/00397911.2010.487174

The reaction of salicylaldehyde with propionic anhydride in the presence of anhydrous K₂CO₃ as catalyst afforded 3-methyl-2H-chromen- 2-one (3-methylcoumarin) in good yields depending on the reaction conditions. The reaction was performed under classic thermal (55% yield) and microwave conditions (91-97% yield).

Full text of DOI:10.1080/00397911.2010.487174

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Efficient Synthesis of 3-Methyl-2H-
chromen-2-one: Classic Versus
Microwave Conditions
a
a
a
Lenka Floreková , Radoslav Flašík , Henrieta Stankovičová &
a
Anton Gáplovský
a
Institute of Chemistry, Faculty of Natural Sciences, Comenius
University , Bratislava , Slovak Republic
Published online: 30 Mar 2011.
To cite this article: Lenka Floreková , Radoslav Flašík , Henrieta Stankovičová & Anton Gáplovský
(2011) Efficient Synthesis of 3-Methyl-2H-chromen-2-one: Classic Versus Microwave Conditions,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:10, 1514-1519, DOI: 10.1080/00397911.2010.487174
To link to this article: http://dx.doi.org/10.1080/00397911.2010.487174
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Synthetic Communications , 41: 1514–1519, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.487174
EFFICIENT SYNTHESIS OF 3-METHYL-2H-CHROMEN-
-ONE: CLASSIC VERSUS MICROWAVE CONDITIONS
2
Lenka Florekov a´ , Radoslav Fla ꢀs ´ı k, Henrieta Stankovi cˇ ov a´ , and
Anton G a´ plovsk y´
Institute of Chemistry, Faculty of Natural Sciences, Comenius University,
Bratislava, Slovak Republic
GRAPHICAL ABSTRACT
Abstract The reaction of salicylaldehyde with propionic anhydride in the presence of
2 3
anhydrous K CO as catalyst afforded 3-methyl-2H-chromen-2-one (3-methylcoumarin)
in good yields depending on the reaction conditions. The reaction was performed under
classic thermal (55% yield) and microwave conditions (91–97% yield).
Keywords Aldol condensation; 3-methylcoumarin; microwave; Perkin reaction
INTRODUCTION
Coumarin derivatives are well known as versatile molecules, not only for their
interesting fluorescent properties, which change drastically with substituents and
[1]
their introduced positions, but also for their usefulness as precursors for many
heterocyclic compounds.
3-Methyl-2H-chromen-2-one (3-methylcoumarin) 1 is an important building
block in organic synthesis. A variety of synthetic methods for preparation of substi-
tuted 3-methylcoumarins are known, such as Baylis–Hillman reaction of O-benzylated
[2]
salicylaldehydes, thermal transformations (rearrangements) of a-aryloxymethyl-
acrylic acids and their derivatives leading to the formation of ‘‘ene’’ dimers, regiose-
[
3]
lective nucleophilic addition of organolithium, Grignard, and hydride reagents to
[
4]
a-phenylsulfanyl-a,b-unsaturated oxazolines, rhodium-catalyzed cyclic carbonyla-
[5]
tion of 2-alkynylphenols, Wittig–Horner reaction of b-hydroxyoxo compounds
and phosphonopropionic acid, and modified Perkin reaction of carboxylic acids
[6]
[7]
and salicylaldehydes. A majority of reported syntheses have disadvatages; they
[
either suffer unsatisfactory yields or require multistep synthesis. We needed to
8]
Received December 22, 2009.
Address correspondence to Henrieta Stankovi cˇ ov a´ , Institute of Chemistry, Faculty of Natural
Sciences, Comenius University, Mlynsk a´ dolina CH-2, 842 15 Bratislava, Slovak Republic. E-mail:
stankovh@fns.uniba.sk
1
514

EFFICIENT SYNTHESIS OF 3-METHYL-2H-CHROMEN-2-ONE
1515
prepare 3-methyl-2H-chromen-2-one 1 in multigram quantities. Here we describe an
efficient synthesis of coumarin 1 from readily available starting compounds.
RESULTS AND DISCUSSION
Synthesis Under Classic Conditions
The synthesis of 3-methyl-2H-chromen-2-one 1 was performed under modified
conditions of the Perkin reaction. Reaction of salicylaldehyde 2 (method A) or its
sodium salt 3 (method B) with propionic anhydride in the presence of anhydrous
K CO as catalyst afforded 3-methyl-2H-chromen-2-one 1 (Scheme 1). It is known
2
3
that a larger amount of anhydride is required to give moderate yields in the Perkin
[
9]
reaction. We used a large excess of propionic anhydride for the reaction under
thermal conditions. The yields of both methods were comparable (Table 1, entries
I and II). The poor yield of 1 was obtained probably because of the formation of
E-phenylpropenoic acid, which does not cyclize to the lactone ring. The reaction
of equimolar amounts of starting compounds resulted in poor and unsatisfactory
yield of product.
[
10]
There is a variety of catalysts suitable for the Perkin reaction. Potassium car-
bonate proved to be a good catalyst for the synthesis of 3-substituted 2H-chromen-
[
11]
[12]
2
-ones
and for the synthesis of 3-alkyl-2H-chromen-2-ones in ionic liquids.
It
worked well also for synthesis of chromene 1. When we used pyridine as catalyst
instead of K CO (method C), the reaction yielded 6H,12H-6,12-epoxidiben-
2
3
zo[bf][1,5]dioxocine 4, and no 3-methyl-2H-chromen-2-one 1 was isolated in that
case. We also have not isolated 2-formylphenyl propionate from the reaction mixture.
It was not a component of liquid residuals distilled off from the reaction mixture. We
expected the formation of this ester, as it can be prepared from salicylaldehyde 2 and
Scheme 1. Synthesis of 3-methyl-2H-chromen-2-one.

´
L. FLOREKOVA ET AL.
1516
Table 1. Effect of reaction mixture composition and reaction time on yield of 3-methyl-2-oxo-2H-
chromene 1
Ratio of starting compounds
aldehyde=anhydride=catalyst
n
aldehyde
n
anhydride
Reaction
time
Yield
(%)
Entry
(mol)
(mol)
Method
I
1:3:0.05
1:12:0.05
1:1:0.05
0.082
0.045
0.047
0.288
0.192
0.288
0.047
0.029
0.047
0.096
0.23
0.54
16 h
16 h
A
B
55
56
14
62
51
73
91
55
97
45
II
III
IV
V
0.047
0.288
0.192
0.315
0.076
0.022
0.036
0.072
65 min
70 min
70 min
95 min
65 min
65 min
65 min
30 min
D
D
D
D
D
D
D
D
1:1:0.05
1:1:0.03
VI
VII
VIII
IX
X
1:1.1:0.08
1:1.6:0.05
1:0.76:0.13
1:0.76:0.05
1:0.75:0.04
[
13]
propionic anhydride in the presence of pyridine.
reaction conditions was reported.
Formation of 4 under different
[14]
Synthesis Under Microwave Conditions
Microwave irradiation has proved to be extremely useful for promoting and
simplifying many condensation reactions, which can be carried out both under sol-
vent and solvent-free conditions. The microwave irradiation shortened the reaction
time of the Perkin reaction of benzaldehydes with acetic anhydride in the presence of
[
15]
cesium salts as catalysts by 60–80 times over classical heating. The yield of unsub-
[
15]
stituted 2H-chromen-2-one obtained this way (48%) is comparable with the yield
of 3-methyl-2H-chromen-2-one 1 obtained by method A (55%). The Perkin reaction
of less reactive anhydrides (propionic and butyric) with benzaldehydes led to poor
[15]
yields (11–14%). Contrary to these reported data, the studied reaction of salicylal-
dehyde 2 with propionic anhydride in the presence of anhydrous K CO as catalyst
2
3
carried out under microwave conditions (method D) afforded 3-methyl-2H-
chromen-2-one 1 in significantly greater yields (Table 1, entries IV, VI, VII, and
IX). This yield is also greater in comparisom with yields of reactions performed
under thermal conditions. Also the reaction time is considerably shorter, about
1
6-fold. Fast and uniform overheating of reaction mixture caused by microwave
irradiation results in decreasing the content of polar low-boiling compounds (e.g.,
water) in reaction mixture; thus, the reaction equilibrium is shifted toward
3
at temperatures over 180 C (to about 185 C; measured by temperature sensor of
-methyl-2H-chromen-2-one 1. The reaction in a microwave oven was performed
ꢀ
ꢀ
ꢀ
the oven). Decrease of reaction temperatute to 170 C led to a decrease in the yield
of product by 15%.
Concentration of catalyst influences the yield of 3-methyl-2H-chromen-2-one
. We have found that the amount of catalyst of 5% of 2 led to the best yields. A
1
greater amount of catalyst (Table 1, entry VI) caused sintering of reaction mixture,
and the isolation of pure chromene was difficult, which resulted in lower yield of
compound 2. Lower amount of catalyst (Table 1, entry V) led to longer reaction time
and poor yield.

EFFICIENT SYNTHESIS OF 3-METHYL-2H-CHROMEN-2-ONE
1517
Ratio of starting compounds also influences the yield of the reaction. There are
[
16,17]
two proposed mechanisms for the Perkin reaction.
The first proposes a forma-
[16]
[9]
and thus an excess of anhydride is necessary.
tion of enolate from anhydride,
We have found that the molar ratio of aldehyde=anhydride 1:1.6 gives the best
results (Table I, entry VII). This finding is the same as for synthesis of unsubstituted
[18]
coumarin under thermal conditions. The second mechanism proposes a formation
[17]
of gem-dicarboxylate, when the use of an excess of aldehyde results in better yield.
We performed the condensation reaction with 25% excess of salicylaldehyde, and we
have obtained 97% yield of 3-methyl-2H-chromen-2-one 1 (Table 1, entry IX). The
reaction with equimolar ratio of reactants under microwave conditions resulted in
greater yield (Table 1, entry IV) than the the reaction performed with excess of
anhydride under thermal conditions.
CONCLUSION
To conclude, we have found suitable reaction condition for synthesis of
-methyl-2H-chromen-2-one 1 in multigram amounts. The reaction of salicylalde-
3
hyde 2 with propionic anhydride in the presence of anhydrous K CO as catalyst
2
3
under microwave condition, depending on the ratio of starting compounds, afforded
-methyl-2H-chromen-2-one 1 in 91–97% yield.
3
EXPERIMENTAL
Melting points (uncorrected) were measured on a Kofler hot stage. The spectra
were recorded on a 300-MHz Varian Gemini 200 spectrometer in CDCl with
3
tetramethylsilane (TMS) as internal standard. All microwave-assisted reactions were
carried out in a Prolabo Synthewave 402 microwave oven in the single-mode cavity
reactor. Reaction course was monitored using thin-layer chromatography (TLC)
(silica gel; eluent ethyl acetate=hexane 3:1).
Materials
Commercial chemicals and solvents were purchased from the major chemical
suppliers as highest purity grade.
Method A
Mixture of salicylaldehyde 2 (81.89 mmol), propionic anhydride (230.5 mmol),
and K CO (4 mmol) was refluxed until the color of the reaction mixture became
2
3
brown (16 h). The excess of propionic anhydride was distilled off. The residue was
poured into crushed ice, and the pH was adjusted to 7 using NaHCO . The precipi-
3
tate was filtered off, washed with water, dried, and recrystallized from a mixture of
hexane=ethyl acetate (4:1) to give 7.18 g (55%) of 3-methyl-2H-chromen-2-one 1 as
ꢀ
white needles: mp 90–91 C.
1
H NMR (300 MHz, CDCl ) d 2.22 (d, 3H, J ¼ 1.47 Hz, CH ), 7.22–7.33 (m,
3
3
2
H, Ar-H), 7.40–7.49 (m, 2H, Ar-H), 7.52 (s, 1H, H-4).

´
L. FLOREKOVA ET AL.
1518
Method B
Salicylaldehyde 2 (70.42 mmol) was added to the solution of NaOH (125 mmol)
in EtOH (50 ml). A precipitate was formed immediately. The salt was filtered off and
dried to give 8.98 g (89%) of sodium 2-formylphenoxide 3. Consequently, the
solution of sodium 2-formylphenoxide 3 (45.13 mmol), propionic anhydride
(0.54 mol), and K CO (2.25 mmol) was refluxed for 16 h. After cooling, the excess
of propionic anhydride was distilled off. The residue was poured into crushed ice,
2 3
and the pH was adjusted to 7 using NaHCO . The precipitate was filtered off,
3
washed with water, dried, and recrystallized from a mixture of hexane=ethyl acetate
4
9
:1 to give 4.04 g (56%) of 3-methyl-2H-chromen-2-one 1 as white needles: mp
ꢀ
0–91 C.
Method C
The mixture of salicylaldehyde 2 (4.7 mmol), propionic anhydride (16.9 mmol),
and a drop of pyridine was refluxed until the color of the solution turned brown
9 h). After cooling, the unreacted starting material was distilled off. The residue
was purified by column chromatography (hexane=chloroform 1:3) to give 0.04 g
(
(
1
6%) of 6H,12H-6,12-epoxido-dibenzo[bf][1,5]dioxocine 4 as white needles: mp
[7]
ꢀ
ꢀ
29–130 C (mp ¼ 130–131 C).
1
H NMR (300 MHz, CDCl ) d 6.34 (s, 2H, CH), 6.86 (d, 1H, J ¼ 8.26 Hz,
3
Ar-H), 6.94–6.99 (dt, 2H, J ¼ 6.43, 1.08 Hz, Ar-H), 7.21–7.31 (m, 4H, Ar-H).
Method D: General Procedure
The mixture of salicylaldehyde 2, propionic anhydride, and K CO was heated
2
3
ꢀ
under microwave irradiation to 180 C for the time given in Table 1. The solution
was poured into crushed ice, and the pH was adjusted to 7 using NaHCO . The
3
precipitate was filtered off, washed with water, dried, and recrystallized from ethanol
to give 3-methyl-2H-chromen-2-one 1 as white needles in yields given in Table 1, mp
ꢀ
9
0–91 C.
ACKNOWLEDGMENTS
This work was supported by grants from the Slovak Grant Agency for Science
VEGA 1=0639=08) and the Slovak Research and Development Agency (APVV-
(
0
128-07).
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