A 'one pot' synthesis of 2-aryl-4H-1-benzopyran-4-ones under coupled microwave phase transfer catalysis (PTC) and ultrasonic irradiation PTC

Article abstract of DOI:10.1002/jhet.5570450246

(Chemical Equation Presented) A 'one pot' synthesis of 2-aryl-4H-1- benzopyran-4-ones (3a-3f) is being reported. A mixture of o-hydroxyacetophenone, aroyl chloride, powdered n-tetrabutylammonium hydrogensulphate (n-TBAHSO ₄) and potassium hydroxide (KOH) were either irradiated by microwaves or sonicated in an ultrasonic cleaning bath to afford flavones directly. On the contrary, conventional liquid-liquid Phase Transfer Catalysis (PTC) using benzene as organic phase and aqueous KOH as the second phase afforded first β-diketones in accordance with Baker-Venkataraman synthesis which upon cyclization by p-toluenesulphonic acid (p-TSA) gave desired flavones in the next step. PTC coupled with microwaves or ultrasound show enhanced yields, the clean reaction conditions require less time, and have easier workup protocol. All synthesized compounds were characterized by their Proton Magnetic Resonance (PMR), IR, FAB Mass and elemental analyses.

Full text of DOI:10.1002/jhet.5570450246

Mar-Apr 2008
589
A 'One Pot' Synthesis of 2-Aryl-4H-1-benzopyran-4-ones Under
Coupled Microwave Phase Transfer Catalysis (PTC) and Ultrasonic
Irradiation PTC
Vijai N. Pathak,1,• Ragini Gupta2 and Bindu Varshney1
1Centre of Advanced Studies, Department of Chemistry, University of Rajasthan,
Jaipur 302 004, India.
2Department of Chemistry, Malaviya National Institute of Technology,
Jaipur 302 017, India
Received March 28, 2007
H
O
O
C
O
1. n - TBAHSO4
+
(CH2)n R / Ar
C
Cl
2. KOH
i / ii / iii
R1
1
2
n = 0,1...
R = CH3
i. Conventional
ii. Ultrasound Irradiation
iii. Microwave Irradiation
O
O
(CH2)n
R2
R / Ar
Ar =
R1
R3
R1, R2, R3 = H, H, H; H, H, 2 - Cl, H, 4 - Cl, H; F, H
3
A 'one pot' synthesis of 2-aryl-4H-1-benzopyran-4-ones (3a-3f) is being reported. A mixture of o-
hydroxyacetophenone, aroyl chloride, powdered n-tetrabutylammonium hydrogensulphate (n-TBAHSO4)
and potassium hydroxide (KOH) were either irradiated by microwaves or sonicated in an ultrasonic
cleaning bath to afford flavones directly. On the contrary, conventional liquid-liquid Phase Transfer
Catalysis (PTC) using benzene as organic phase and aqueous KOH as the second phase afforded first β-
diketones in accordance with Baker-Venkataraman synthesis which upon cyclization by p-
toluenesulphonic acid (p-TSA) gave desired flavones in the next step. PTC coupled with microwaves or
ultrasound show enhanced yields, the clean reaction conditions require less time, and have easier workup
protocol. All synthesized compounds were characterized by their Proton Magnetic Resonance (PMR), IR,
FAB Mass and elemental analyses.
J. Heterocyclic Chem., 45, 589 (2008).
[18]. Halogenated flavones exhibit structure-dependent
aryl hydrocarbon receptor (AhR) agonist and antagonist
activities comparable to that observed for 2,3,7,8-
tetrachlorodibenzo-p-dioxin TCDD [19]. One of the most
recent study reports the effect of some flavonoids on the
central nervous system [20]. Halogenated flavanones are
considered potential benzodiazepine receptor ligands [21].
The general method to obtain flavones are the cyclization
of 1,3-diphenylpropane-1,3-diones or 2'-hydroxychalcones,
which are prepared from 2'-hydroxyacetophenones and
benzoylating reagents or benzaldehydes [22]. In the Baker-
Venkataraman process [23,24], 2'-hydroxyacetophenones
are converted into benzoyl esters, which are rearranged
with bases to form 1,3-diphenylpropane-1,3-diones,
followed by cyclization with sodium acetate [23a] or
sulphuric acid [23b,c] in acetic acid, I2-DMSO [25], and
CoIII(salpr)(OH) [(Salpr) = N1,N7–4–azaheptamethylenebis-
(salicylideneiminato)] [26] to yield flavones in three steps.
Although the reaction of 2'-hydroxyacetophenones and
benzoyl chlorides [27] or methyl benzoates [28] with bases
affords 1,3-diphenylpropane-1,3-diones directly, these
methods required excess benzoylating reagents or bases.
INTRODUCTION
Flavones are a class of naturally occurring compounds
present in a wide variety of plants, seeds, citrus fruits, olive
oil, tea and red wine and are commonly consumed with
human diet [1-2]. Most of the current synthesis for new
flavanoids are based on the pioneer work developed by
Robinson [3] and Venkataraman [4] and despite the number
of steps involved in the both these methods, they still
constitute the most popular methodologies currently used for
preparation of flavanoids. These synthetic effects are due
both to their chemotaxonomical interest as biological
markers [5] and to the increasing importance of their
multiple biological activities: leishmanicidal activity [6],
ovipositor stimulant phytoalexins [7], anti-HIV [8],
vasodilator [9], anti-viral [10], anti-oxidants [11], bactericidal
[12], DNA cleavage [13], anti-inflammatory [14], anti-
mutagenic [15], anti-allergic [16] and anti-cancer [17].
The incorporation of electronegative elements, such as
halogens, in the flavonoid structure, introduces new
patterns of biological properties. 4',6-Dichloroflavon has
been reported to be a potent antirhinovirus compound

590
V. N. Pathak, R. Gupta and B. Varshney
Vol 45
The oxidative cyclodehydration of 2-hydroxychalcones
with NiCl2/Zn/KI [29], NaIO4-DMSO [30] and iodoso-
benzene diacetate [31] also leads to the formation of
flavones, but this process requires high reaction
temperature. Other methods to synthesize flavones include
the coupling of 2-iodophenols with phenylacetylenes in the
presence of secondary amine and PdCl2 (dppf) [32], but
only a few examples of flavones from these techniques
have been reported.
All the above discussed methods are cumbersome
requiring two or three steps and involve lengthy work-up
procedures. So, now we wish to report a simple 'One Pot'
strategy for synthesizing 2-aryl-4H-1-benzopyran-4-ones
(3a-3f) (Scheme 1) coupling PTC with either microwave
or ultrasound irradiation.
PTC, microwave and ultrasound (non-conventional
methods) all are now recognized as environmentally
benign alternatives to conventional methods.
In conclusion, we report three comparative strategies
for the preparation of 2-aryl-4H-1-benzopyran-4-ones. It
is observed that out of the three methods, microwave
irradiated reactions occur in faster (<10 minutes), give
higher yield (>80%), have simpler reaction procedures
and eliminate the use of solvents. When the reaction
mixture was irradiated in domestic microwave for a
longer time (greater than 10 minutes) and in excess
amount of aroyl chloride (> 12 mmol), the aroylation also
occurred at position – 3 in the presence of PT catalyst.
RESULTS AND DISCUSSION
Phase Transfer Catalysis (PTC) allows one to perform
many reactions that otherwise proceed unsatisfactorily or
do not proceed at all due to the reactants being present in
different phases. It minimizes the two important
deactivating forces viz. solvation and ion pairing. PTC is
now well established as a 'Green Chemistry Technique'.
PTC coupled with non-conventional energy sources like
microwaves and ultrasonic irradiations offers the advantage
of accomplishing reaction at ambient pressure, thus
providing unique chemical process with special attributes
such as enhanced reaction rates, higher yields and the
associated ease of manipulation. Heterogenous reactions
facilitated by supported reagents on inorganic oxide
surfaces have received attention in recent years [33].
In light of above observations and in continuation to
our previous work on bioactive fluorinated/non-
fluorinated heterocycles and PTC, we thought it
worthwhile to synthesize derivatives of these biologically
useful heterocycles by using a simple, convenient and
mild phase transfer catalyzed heterocyclization approach
leading to the synthesis of desired product via PTC
induced by microwaves or ultrasound irradiation. Since
the compounds may be potentially bioactive they would
be sent for screening for their anti-inflammatory and anti-
tumor activities.
2-Aryl-4H-1-benzopyran-4-ones (3a-3f) were synthe-
sized by employing various reaction conditions viz.,
classical, ultrasonic radiations and microwave PTC
approach. In the classical approach o-hydroxyacetophen-
one/5-fluoro-2-hydroxyacetophenone (1) was treated with
substituted aroyl chlorides (2) under PTC conditions to
give β-diketones which in turn on cyclization with p-
toluenesulphonic acid (p – TSA) afforded the substituted
2-aryl-4H-1-benzopyran-4-ones (3) in good yield.
Scheme 1
H
O
O
C
O
1. n - TBAHSO4
R / Ar
+
(CH2)n
C
Cl
2. KOH
i / ii / iii
R1
1
2
n = 0,1...
R = CH3
i. Conventional
ii. Ultrasound Irradiation
iii. Microwave Irradiation
O
(CH2)n
R2
R / Ar
Ar =
R1
R3
O
R1, R2, R3 = H, H, H; H, H, 2 - Cl,
H, 4 - Cl, H; F, H
3
Table 1: Physical and Analytical Data of compounds (3a-f)
Compd. No.
R
R1
R2
R3
n
Mol. For.
m.p.Ref
Analysis %
Yield %
Calcd./Found
°C
95-9624
C
H
i
70
ii
75
iii
81
3a
3b
3c
3d
3e
3f
-
-
-
-
-
H
H
H
H
0
0
0
0
1
8
C15H10O2
C15H9O2Cl
C15H9O2Cl
C15H9O2F
C16H12O2
C19H26O2
81.08
81.12
70.17
70.26
70.17
70.26
75.00
75.25
81.36
81.47
79.72
79.64
4.50
4.51
3.51
3.50
3.51
3.52
3.75
3.74
5.08
5.07
9.09
9.10
H
H
F
2 -Cl
H
185-187
251-25334
99-103
72
71
74
75
69
76
74
77
79
71
83
85
84
85
79
4 -Cl
H
H
H
H
H
H
146-149
Viscous
CH3
H
H
i) Conventional, ii) Ultrasonic Irradiation, iii) Microwave Irradiation, *Reference Number

Mar-Apr 2008
A 'One Pot' Synthesis of 2-Aryl-4H-1-benzopyran-4-ones
591
further purification. 5-Fluoro-2-hydroxyacetophenone was
prepared by literature method [33].
In the ultrasonic approach o-hydroxyacetophenone/5-
fluoro-2-hydroxyacetophenone (1) and substituted aroyl
chlorides (2) under PTC conditions were sonicated for 2-3
hours to afford the desired products (3) in higher yield
and shorter reaction time than the classical approach.
The same reactants without benzene were thoroughly
mixed and irradiated for 250-300 seconds in a domestic
microwave oven to afford the desired products in higher
yield and lesser time in contrast to conventional process.
The results are presented in Table 1. All the synthesized
compounds were characterized on the basis of their
analytical and spectral (IR, 1H NMR and FAB Mass) data
which agreed well with assigned structures (Table – 2).
General Procedures for the preparation of 2-aryl-4H-1-
benzopyran-4-ones (3a-3f).
Method (i) o-hydroxyacetophenone/5-fluoro-2-hydroxy-
aceto-phenone (1) (3.0 mmol ) and substituted aroyl chlorides
(2) (3.6 mmol) in benzene (20 mL) were magnetically stirred
at 80 °C with KOH solution (50%; 20 mL) in the presence of
n-TBAHSO4 (1.5 mmol, 0.51 g) for 2-3 hours until the starting
acetophenone and the first formed o-aroyloxyacetophenone
disappeared (TLC). During this period the benzene solution
acquired a deep yellow to orange color. The benzene layer was
separated, washed thoroughly with water (3*100 mL) and from
the separated benzene layer the water was removed by
Table 2: Spectroscopic data of 2-aryl-3H-1-benzopyran-4-one (3a-f)
Compd.
No.
IR νmax (cm-1)
(KBr)
1H NMR δ (ppm)
(CDCl3)
FAB Mass m/z
(M++1)
1
3071(aromatic C-H str.), 1646 (>C=O), (DMSO-d6): 8.26 (dd, J = 7.9 Hz, J = 1.62 Hz,
2
3a
1606 (aromatic >C=C< str.), 1129 (C-O-C)
1H), 7.94-7.98 (m, 2H), 7.62-7.76 (m, 1H), 7.52-
7.59 (m, 4H), 7.43-7.48 (m, 1H), 6.9 (s, 1H)
223
2
3b
3090 (aromatic C-H str.), 1642 (>C=O), (DMSO-d6): 8.25 (dd, 1J = 7.9 Hz, J =1.62 Hz,
1606 (aromatic >C=C< str.), 1090 (C-O-C), 1H), 7.74 (d, J = 7.14 Hz, 2H), 7.70-7.75 (m, 1H),
828 (C-Cl)
7.58 (d, J = 8.61 Hz, 1H), 7.42-7.47 (m, 1H), 7.52
(d, J = 7.14 Hz, 2H), 6.8 (s, 1H)
257 / 259
1
3c
3142 (aromatic C-H str.), 1647 (>C=O), (DMSO-d6): 8.1 (dd, J =7.9 Hz, 2J = 1.62 Hz,
1590 (aromatic >C=C< str.), 1010 (C-O-C), 1H), 7.74 (d, J = 7.74 Hz, 2H), 7.73-7.76 (m, 1H),
875 (C-Cl)
7.65 (d, J = 8.4 Hz, 1H), 7.40-7.50 (m, 1H), 7.47
(d, J = 7.14 Hz, 2H), 7.01 (s, 1H)
257 / 259
241
3d
3e
3065 (aromatic C-H str.), 1675 (>C=O), (DMSO-d6): 8.1 (d, J = 7.30, 1H), 7.87-7.92 (m,
1600 (aromatic >C=C< str.), 1130 (C-O-C), 1H), 7.55 (d, J = 6.06 Hz, 2H), 7.26-7.49(m, 5H),
1075(C-F)
3072 (aromatic C-H str.), 2875 (aliphatic C- (DMSO-d6): 7.69 (dd, 1J = 8.04 Hz, 2J = 1.44 Hz,
str.), 1608 (C-O-C), 1500 (aromatic 1H), 7.52-7.58 (m, 2H), 7.42-7.46 (m, 1H), 7.30-
6.8 (s, 1H)
H
>C=C< str.), 1010 (>C=O)
7.40 (d, J = 8.4 Hz, 1H), 7.40-7.50 (m, 5H), 7.01
(s, 1H), 3.01 (s, 2H), 2.42 (s, 2H)
237
287
3f
3072 (aromatic C-H str.), 1646 (>C=O), (DMSO-d6): 8.1 (dd, 1J = 7.98 Hz, 2J = 1.42 Hz,
1606 (aromatic >C=C< str.), 1129 (C-O-C)
1H), 7.51-7.64 (m, 2H), 7.41-7.48 (m, 1H), 6.69
(s, 1H), 1.36-1.44 (m, 2H), 1.73-1.78 (m, 16H)
azeotropic distillation. To this reaction mixture p- toluene-
sulphonic acid (9.0 mmol, 1.71 g) in dry benzene (25-50 mL)
was added. The reaction mixture was further refluxed and the
water generated in the reaction was azeotropically removed
(30-45 minutes). Excess p-toluenesulphonic acid was extracted
from the benzene solution with sodium hydrogen carbonate
solution (8%; 50 mL). Benzene was distilled off and the
residue dried under vacuo over phosphorus pentoxide. The
residue was recrystallized from ethyl acetate - light petroleum
ether or benzene - light petroleum ether to give the desired
product.
Method (ii): A mixture of n-TBAHSO4 (10 mmol, 3.39 g)
and KOH (20 mmol, 1.12 g) was grinded together in a mortar.
Then this mixture was transferred into a pyrex conical flask (100
mL). o-Hydroxyacetophenone / 5-fluoro-2-hydroxyacetophen-
one (1) (10 mmol) and substituted aroyl chloride (2) (12 mmol)
were added to it and irradiated in an ultrasonic cleaning bath for
120-150 minutes at a temperature of 35-40 °C. The reaction
flask was located in the maximum energy area in the cleaner.
The bath temperature was controlled by the addition or removal
EXPERIMENTAL
All the melting points were determined in open glass capillary
tubes and are uncorrected. The IR spectra (νmax in cm-1) were
recorded on a Perkin Elmer 557 grating infrared spectro-
photometer in KBr pellets. PMR spectra were recorded on JEOL
AL 300 spectrometer (300 MHz) using CDCl3 as a solvent. TMS
was used as internal standard (chemical shift in δ, ppm) at
Department of Chemistry, University of Rajasthan, Jaipur. The
FAB mass spectra were recorded on a JEOL SX 102/DA-6000
Mass spectrometer / Data system using Argon / Xenon (6KV,
10mA) as the FAB gas at Central Drug Research Institute
(CDRI), Lucknow. Reactions were carried out in an LG MS-
194 A household microwave oven with maximum 800 power.
Sonication was carried out in a Toshion, Model SW 4 cleaner
with a frequency of 37 Hz and a power of 150 watts. The purity
of the compounds was checked by TLC using silica gel (60 –
120 mesh) as adsorbent, UV light or iodine accomplished
visualization. o-Hydroxyacetophenone, aroyl chlorides, KOH, n-
TBAHSO4 are all commercial products and were used without

592
V. N. Pathak, R. Gupta and B. Varshney
Vol 45
Phytother. Res. 2000, 14, 89; Bae, E. A.; Han, M. J.; Lee, M.; Kim, D.
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of water. The progress of reaction was monitored by TLC using
C6H6:EtOAc:90:10 as solvent system. After cooling to room
temperature, HCl (2 N; 25 mL) was added, the reaction was
extracted with chloroform and the product was purified by
column chromatography using silica gel (60 – 120 mesh) as
stationary phase and solvents of increasing polarity as mobile
phase. Pure flavone was obtained in benzene: pet-ether (4:1) as
yellow crystalline needles.
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and KOH (20 mmol, 1.12 g) was grinded together in a mortar.
Then this mixture was transferred into a conical flask (100 mL).
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(10 mmol) and substituted aroyl chloride (2) (12 mmol) was
added to it and irradiated with microwaves for 5-6 minutes at
full power (800 W). Final temperature of the reaction was
measured with the help of a thermometer at the end of the
reaction. The progress of reaction was monitored by TLC using
C6H6:EtOAc: 90:10 as solvent system. After cooling to room
temperature, HCl (2 N; 25 mL) was added, the reaction was
extracted with chloroform and the product was purified by
column chromatography using silica gel (60 – 120 mesh) as
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(4:1) as yellow crystalline needles.
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*
Corresponding author. Tel.: +91 94142 55384; e-mail:
pathakvijain@yahoo.com
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