Efficient synthesis of 3-methyl-flavanones and evaluation of their anti-bacterial activity

Article abstract of DOI:10.1002/cjoc.201200254

A series of 2-phenyl-2,3-dihydrochromon-4-one derivatives (flavanone derivatives) were synthesized by silica gel assisted isomerization of several α-methyl-2′-hydroxy chalcones in 74%-88% yield. These flavanones were further oxidized to 3-methyl flavones by using iodine in dimethyl sulphoxide at 60°C in presence of acid. The newly synthesized derivatives were evaluated for in vitro study against Staphylococcus aureus, Micrococcus luteus and Staphylococcus epidermis.

Full text of DOI:10.1002/cjoc.201200254

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DOI: 10.1002/cjoc.201200254
Efficient Synthesis of 3-Methyl-Flavanones and Evaluation of
Their Anti-Bacterial Activity
Nawghare, Beena
Funde, Sharad
Raheem, Abdul
Lokhande, Pradeep*
The Centre for Advanced Studies, Department of Chemistry, University of Pune, Pune 411 007, India
A series of 2-phenyl-2,3-dihydrochromon-4-one derivatives (flavanone derivatives) were synthesized by silica
gel assisted isomerization of several α-methyl-2'-hydroxy chalcones in 74%—88% yield. These flavanones were
further oxidized to 3-methyl flavones by using iodine in dimethyl sulphoxide at 60 ℃ in presence of acid. The
newly synthesized derivatives were evaluated for in vitro study against Staphylococcus aureus, Micrococcus luteus
and Staphylococcus epidermis.
Keywords cyclization, oxidation, chalcones, silica gel, 3-methyl-flavanones
Introduction
formation of flavanones. Yields of these reactions were
low to moderate. Various solid catalysts have been ap-
plied for flavonoid synthesis, such as magnesium ox-
ide,[20] zinc, alumina, barium hydroxides, hydrotalcites
and natural phosphates modified with NaNO3 or KF.
However, most of them require the use of expensive
toxic solvents to facilitate the heat and mass transfer in
the liquid phase reaction systems.[21]
Flavonoids are polyphenolic compounds that are
widely distributed in plants and have attracted consid-
erable attention due to their numerous pharmacological
applications. Flavonoids are occurring in nature in free
state or as glycosides associated with tannins (fla-
vanoids). The derivatives of phenol present as glycosi-
dal form and chemically they are derivatives of chro-
mone ring.[1,2] Natural and synthetic flavanoids have
attracted considerable attention because of their inter-
esting biological activities, including anti-oxidant, anti-
fungal, anti-bacterial, anti-inflammatory, antitumor,
anti-asthmatic, antiviral, antihypertensive, estrogenic,
antixiolytic, diuretic activity and inhibition of hormone-
dependent proliferation of cancer cells.[3-7] Flavanoids
inhibit xanthine-oxidase enzyme and have superoxide-
scavenging activities. Therefore they could be a prom-
ising remedy for human gout and ischemia by decreas-
ing both uric acid and superoxide concentration in hu-
man tissues.
The reaction of flavanone synthesis can be per-
formed using acids,[8] bases,[9,10] light,[11] heat,[12] mi-
crowave[13] or electrons.[14] There are numerous meth-
ods available for the synthesis of flavones like Kosta-
necki,[15] Allan Robinson,[16] Mahal-Venkataraman,[17]
oxidation of 2'-hydroxychalcone, the Wheeler method
and others. Many of these methods for synthesis of fla-
vanones and flavones required more amount of heating
during the reaction and the yields of the products ob-
tained were less (50% — 60%).[18] The reaction of
2'-hydroxychalcones with palladium(II) acetate, Co
(salpr) under oxygen atmosphere and potassium ferri-
cyanide using phase transfer catalysts[19] leads to the
The acid catalyzed cyclization can be carried out by
refluxing the chalcone in acetic acid, in the presence of
[22]
acid catalyst such as H2SO4 or H3PO4 and ethanol or
other suitable solvents. Basic conditions are seldomly
used due to decomposition or retroaldol reaction. Al-
though 2'-hydroxychalcones may also be cyclized to
flavanones with acidic (H2SO4 in methanol, CH3COOH
and phosphoric acid), basic (pyridine and DBU) re-
agents and microwave irradiation, most of the employed
methods require prolonged reaction time at high tem-
perature.
Alternatively flavanones can be prepared from the
oxidative cyclization of cinnamic acids and phenols
with phosphoric acid or 2'-hydroxyacetophenones and
benzaldehydes with piperdine in one step. But the yields
of the former are very low and the latter are not applica-
ble for flavanones.
Synthesis of flavones is reported using heterogene-
ous catalyst molecular iodine loaded neutral alumina
under microwave irradiations.[23] CuI catalyzed cascade
oxa-Michael-oxidation, using chalcones as substrates,
mediated by the ionic liquid [bmim][NTf2] also gives
flavones.[24] But this method takes more time even at
high temperature. Menezes et. al.[25] followed the strat-
egy of using chalcones for the synthesis of flavones.
I2/DMSO/H2SO4 system was used for the synthesis of
*
E-mail: pdlokhande@chem.unipune.ac.in
Received March 15, 2012; accepted April 9, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200254 or from the author.
Chin. J. Chem. 2012, XX, 1—4
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Nawghare et al.
COMMUNICATION
bromo-substituted flavone-like troponoid compounds.[26]
Earlier use of iodine has been reported for dehydroge-
nation of dihydropyridazin-3(2H)-one, deallylation of
allyl-aryl ethers, oxidation of β-anilino-dihydrochal-
cones to β-anilino-chalcones.[27] In this paper, we wish
to report silica gel assisted isomerization of several
α-methyl 2'-hydroxychalcones yielding corresponding
flavanones. These flavanones are converted to 3-methyl
flavones using iodine in dimethyl sulphoxide reagent in
presence of a drop of concentrated sulphuric acid
(Scheme 1).[28]
and reference antibiotics were evaluated against the
Staphylococcus areus, Micrococcus luteus and Staphy-
lococcus epidermis by turbidometric method.[29-31] The
inocula of microorganisms were prepared from 12 h
grown culture. The tested samples were first dissolved
in dimethyl sulphoxide (DMSO), then in Nutrient Broth
to the highest dilution of 25 µg in each well of 96 wells
micro plate.
The final concentration of DMSO in well was less
than 1% (φ). Gentamycin and Penicillin diluted prior in
water were used as reference. The bacterial inocula ap-
plied contained approximately 1.0×105 cells in a final
volume of 200 µL of broth medium.
Experimental
The micro plates were incubated for 24 h at 37 ℃
and optical density was measured at 600 nm. Values are
used for calculation as means of three parallel experi-
ments. IC50 values of the tested samples against patho-
gens were theoretically determined.
Materials
All melting points were determined with an Electro
1
thermal model 9100 apparatus and are uncorrected. H
NMR spectra were recorded on a Varian 300 MHz
spectrophotometer in CDCl3 with TMS as internal stan-
1
dard. The H chemical shifts are reported downfield
Results and Discussion
from TMS. IR spectra were recorded on Shimadzu
FTIR spectrophotometer. All solvents were dried dis-
tilled prior to use.
In present work we have successfully implemented
cyclization technique for synthesis of substituted fla-
vanone derivatives 2a—2m from the substituted chal-
cones 1a — 1m (Scheme 1). The starting materials
α-methyl-2'-hydroxychalcones were prepared from
various substituted acetophenones and substituted ben-
zaldehydes by using methanol and 40% sodium hy-
droxide solution. The 3-methyl flavanones were best
prepared by cyclization of α-methyl-2'-hydroxychal-
cones in dichloromethane and sulphuric acid with silica
gel support at room temperature. The acid catalyzed
cyclization in presence of silica gel support faster and
gave good yield of the flavanones. The method devel-
oped was simple and economical. The reaction was
clean and no byproducts were seen. Since there is no
heating during the entire course of reaction, it reduces
side reactions and decomposition of products. The
yields of the products obtained were comparable to
other methods of the synthesis of flavanones. Com-
pounds 2a—2m gave positive test for flavanones. It did
not give positive ferric chloride test indicating absence
of hydroxyl group.
Typical experimental procedure for 6-chloro-4'-
methoxy-3-methyl flavanone (2a)
To a mineral support silica gel (1 g, 60—230 mesh)
0.2 mL concentrated sulphuric acid was added and then
it is evaporated to dryness for firm adsorption of H2SO4
on silica gel. To this, α-methyl-2'-hydroxychalcone (1a)
(0.1 mmol) was added with 5 mL dry dichloromethane.
The reaction mixture was stirred at room temperature
for 3 h (the reaction was monitored by TLC). Then it is
filtered and the solvent was evaporated to obtain solid
product, which is recrystallized by ethyl acetate. Light
yellow solid. m.p. 101—102 ℃; 1H NMR (CDCl3, 300
MHz) δ: 7.85—7.81 (m, 1H, ArH), 7.41—7.34 (m, 2H,
ArH), 7.24 (s, 1H, ArH), 6.96—6.89 (m, 3H, ArH), 5.00
(d, J＝12 Hz, 1H, CH), 3.83 (s, 3H, OMe), 3.06—2.95
(m, 1H, CH), 1.01 (d, J＝6.6 Hz, 3H, CH3); 13C NMR
(CDCl3) δ: 193.54, 160.14, 159.70, 135.62, 129.64,
128.66, 126.88, 126.52, 121.08, 119.65, 115.71, 114.16,
114.42, 85.39, 55.31, 46.10, 10.19; IR (KBr) ν: 3070
(Ar-H), 2982 (Aliph-C-H), 1681 (C＝O), 1307 (C-O-C)
cm － 1; MS (m/z): 302 (M ＋ ion). Anal. calcd for
C17H15ClO3: C 67.44, H 4.99; found C 67.27, H 4.78.
Recently we have developed a simple method for the
synthesis of flavones by using iodine and dimethyl
sulphoxide reagent. 2'-Allyloxychalcones were oxida-
tively cyclized to flavones by using catalytic amount of
iodine in dimethyl sulphoxide.[28] Using this methodol-
ogy we have converted flavanones 2a—2m to flavones
Antibacterial activity
The antibacterial activities of compounds 2a—2d
Scheme 1 Synthesis of 3-methyl flavanones and its oxidation to 3-methyl flavones using I2-DMSO reagent
R3
R1
R3
R4
R1
R1
R3
R4
OH
CH3
H+, Silica gel
I2 -DMSO
O
O
O
R4
H+, 60 oC, 30 min
DCM, r.t., 3 h
74% － 88%
R2
R2
CH3
CH3
R2
O
O
1a － 1m
3a － 3m
2a － 2m
2
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Chin. J. Chem. 2012, XX, 1—4

Efficient Synthesis of 3-Methyl-Flavanones and Evaluation of Their Anti-Bacterial Activity
in good yields (Table 1). Flavanones 2a—2m were
heated with catalytic amount of iodine and dimethyl
sulphoxide in the presence of a drop of concentrated
sulphuric acid. The oxidation reaction was completed
within 30 min to yield the flavones 3a—3m (Table 2).
showed nearly same values of proton peaks. The values
of coupling constant confirm that C2-H and C3-H pro-
tons are trans in geometry. The downfield absorptions
of C2-H and C3-H protons are due to their attachment to
oxygen atom. A singlet of methoxy group was observed
at δ 3.83. Aromatic protons showed multiplets in the
downfield region of the spectra i.e. at δ 6.80—7.85. The
IR spectra of compounds 2a—2m showed absorptions
Table
1
3-Methyl flavanones obtained from α-methyl
2'-hydroxychalcones using H＋ with silica gel as a mineral sup-
port
nearly at 1307 cm－ due to C—O—C stretching and
1
1681 cm－ due to C＝O stretching. The aliphatic C—H
1
Compd. R1 R2
R3
OCH3
OCH3
OCH3
OCH3
H
R4
Yield of 2a,b/%
showed absorption at 2982 cm－ and aromatic absorp-
1
－
1
2a
2b
2c
2d
2e
2f
H
Cl
H CH3
Cl
H CH3
H
87
86
88
82
83
81
79
74
78
81
80
78
75
tion at 3070 cm .
H
The purity of compounds was checked by GC. The
NMR spectra were consistent with the assigned struc-
tures.
H
OCH3
OCH3
OCH3
Cl
H
H
H
H
Cl
Cl
Cl
Antimicrobial activity
H
Antimicrobial effects of flavone and flavanones and
their derivatives have been extensively researched. It is
well-known that many flavones and their derivatives
exhibit antimicrobial activity. Therefore, our newly
synthesized 3-methyl flavanones have been screened in
vitro for antibacterial activity and structure activity rela-
tionship. The results obtained from antibacterial activity
of flavanones are shown in Table 3. The flavanones
2a—2d at the tested concentration exhibit antibacterial
activity. Higher growth inhibition values were observed
for flavanones against bacterial species S. aureus. The
lowest IC50 values, which indicate the high antibacterial
activity, were found against the S. aureus strain by 2c
and 2d. Compound 2c is more active against Staphylo-
coccus aureus, Micrococcus luteus and Staphylococcus
epidermis.
2g
2h
2i
H
H
Cl OCH2CH＝CH2
CH3
Cl
Cl Cl
Cl Cl
Cl Cl
Cl Cl
H
OCH3
H
2j
OCH3
OCH3
H
2k
2l
H
2m
Cl Cl OCH2CH＝CH2 OCH3
a
b
Isolated yields of the products. Products are characterized by
spectral analysis.
Table 2 Synthesis of flavones by oxidation of 3-methyl fla-
vanones using I2-DMSO reagent
Compd. R1 R2
R3
OCH3
OCH3
OCH3
OCH3
H
R4
H
Yield of 3a,b/%
3a
3b
3c
3d
3e
3f
H
Cl
H CH3
Cl
H CH3
91
89
87
92
93
92
94
91
93
92
90
85
87
Structure-activity relationship suggests that modifi-
cation in flavanones at R4 position by OCH3 was re-
sponsible for the higher antibacterial activity. The pres-
ence of Cl group at R1 position indicates increase in
activity of flavanones.
H
H
OCH3
OCH3
OCH3
Cl
H
H
H
H
Cl
Cl
Cl
H
Table 3 Antimicrobial activity of 3-methyl flavanones as IC50
values against Staphylococcus aureus, Micrococcus luteus and
Staphylococcus epidermis
3g
3h
3i
H
H
Cl OCH2CH＝CH2
CH3
Cl
IC50/(μmol•L－
)
1
Cl Cl
Cl Cl
Cl Cl
Cl Cl
H
OCH3
H
Compd.
3j
OCH3
OCH3
H
Staphylococcus Micrococcus Staphyloccus
aureus
109.11
luteus
171.59
epidermis
154.52
392.95
120.90
266.35
—
3k
3l
2a
2b
H
147.4
44.35
64.21
29.56
—
258.45
79.50
187.45
23.87
—
3m
Cl Cl OCH2CH＝CH2 OCH3
b
a Isolated yields of the products. Products are characterized by
2c
2d
spectral analysis.
Gentamycin
The 1H NMR spectra of compounds 2a—2m showed
three prominent proton peaks near δ 1.01, 3.06 and 5.00.
The spectra of compound 2a showed doublet of
3-methyl proton at δ 0.98—1.01 (J＝6.6 Hz). There was
multiplet of C3-H proton at δ 2.95—3.06 (J＝7.1 Hz).
The spectra also showed doublet of C2-H proton at δ
4.96—5.00 (J＝12.1 Hz). The compounds 2b—2m
Penicillin
84.16
b
a Isolated yields of the products. Products are characterized by
spectral analysis.
Conclusions
The 3-methyl flavanones were easily prepared by
Chin. J. Chem. 2012, XX, 1—4
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3

Nawghare et al.
COMMUNICATION
Lett. 2001, 42, 1403.
cyclization of α-methyl-2'-hydroxychalcones in dichlo-
romethane and sulphuric acid with silica gel support at
room temperature. The method developed for synthesis
of flavanones is economical because of simple proce-
dure and absence of byproducts. And the newly synthe-
sized 3-methyl flavanones containing Cl (R1) and OCH3
(R4) showed higher antibacterial activity.
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