Phase transfer catalysis extends the scope of the Algar-Flynn-Oyamada synthesis of 3-Hydroxyflavones

Article abstract of DOI:10.1071/CH14620

The Algar-Flynn-Oyamada reaction is the classical method to synthesize 3-hydroxyflavones from chalcones. Despite its relative simplicity, the reaction has several drawbacks including variable and often low product yields. We have found that phase transfer

Full text of DOI:10.1071/CH14620

CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 1102–1107
Full Paper
http://dx.doi.org/10.1071/CH14620
Phase Transfer Catalysis Extends The Scope of The
Algar–Flynn–Oyamada Synthesis of 3-Hydroxyflavones
A B
,
A B D
, ,
A B C E
, , ,
Duong Nhu,
Bill C. Hawkins,
and Christopher J. Burns
A
ACRF Chemical Biology Division, Walter and Eliza Hall Institute of Medical Research,
1G Royal Parade, Parkville, Vic. 3052, Australia.
B
Department of Medical Biology, The University of Melbourne, Vic. 3010, Australia.
C
School of Chemistry, The Bio21 Institute, The University of Melbourne, Vic. 3010,
Australia.
D
Current address: Department of Chemistry, University of Otago, PO Box 56,
Dunedin, New Zealand.
E
Corresponding author. Email: burns@wehi.edu.au
The Algar–Flynn–Oyamada reaction is the classical method to synthesize 3-hydroxyflavones from chalcones. Despite its
relative simplicity, the reaction has several drawbacks including variable and often low product yields. We have found
that phase transfer catalysis improves the yields and expands the scope of the Algar–Flynn–Oyamada reaction of a series
of 4-benzyloxy-2-hydroxy chalcones.
Manuscript received: 16 October 2014.
Manuscript accepted: 21 November 2014.
Published online: 23 March 2015.
Introduction
O
O
Flavonoids are a class of polyphenolic compounds found
extensively in nature and widely consumed in food and for
medicinal purposes.[1] They have been shown to possess a
variety of biological activities including anti-cancer,[2,3] anti-
inflammatory,[4] anti-microbial,[5] and anti-viral properties[6]
among others.[7,8] Of the flavanoids, 3-hydroxyflavones
(flavanols, 1) have received considerable attention, not only for
their manifold biological activities,[9–17] but also due to their use
as fluorescent sensors,[18–22] and more recently as synthetic
intermediates for photochemical transformations.[23–27]
OH
R1
R
R
O
OH
R1
2
3
O
OH
The classical route to the preparation of 3-hydroxyflavones is
via the base-induced oxidative cyclization of chalcones (2)
known as the Algar–Flynn–Oyamada (AFO) reaction
(Scheme 1).[28,29] The reaction proceeds via formation of the
dihydroflavanol (3), which is then further oxidized to the desired
product (1), though the precise mechanism is a matter of
continued debate.[30–33] Despite the apparent simplicity of this
reaction, it is capricious and somewhat limited in scope:
complex reaction mixtures are often formed making product
isolation difficult, and product yields are generally poor-to-
moderate.[34] As a consequence, several alternative routes to
3-hydroxyflavones have been devised including oxidation of the
corresponding flavones directly[35] or via borylation of lithiated
flavones and subsequent oxidation and hydrolysis of the inter-
mediate boronate.[36,37] More recently Kraus et al. have reported
a novel base-induced ring-closure/rearrangement reaction of
a-cyanobenzyloxy hydroxyacetate derivatives,[38] while numer-
ous groups have reported variations to the conventional AFO
reaction conditions.[39–41] As part of our research program on
the synthesis and biological evaluation of analogues of the
R
O
R1
1
Scheme 1. AFO reaction.
cytotoxic natural product silvestrol,[42] prepared using a photo-
cycloaddition reaction of 3-hydroxyflavones,[23,24] we required
a robust route to a variety of 7-benzyloxy-3-hydroxyflavones
with variable substitution patterns on the 2-phenyl ring. This
paper describes our preliminary results from this endeavour.
Results and Discussion
Our structure–activity exploration of analogues of the
natural product silvestrol required access to a variety of
3-hydroxyflavones 1a–g.[42] Given the extensive literature on
the AFO reaction and the reported preparation of close analo-
gues to those we required,[43] our initial attempts to prepare this
Journal compilation Ó CSIRO 2015
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Phase Transfer Catalysis in the AFO Reaction
1103
O
O
O
R1
R1
KOH
ϩ
O
OH
O
OH
EtOH/dioxane/H2O
2a–g
4
5a–g
NaOH, H2O2
phase transfer catalyst
EtOH/dioxane/H2O
a
b
c
d
e
f
g
: p-methoxy
: p-methyl
: 3,4-methylenedioxy
: 3,5-dimethoxy
: m-methoxy
: p-Br
: p-OCF3
O
OH
O
O
R1
1a–g
Scheme 2. Synthesis of 7-benzyloxy-3-hydroxyflavones.
Table 1. Yields of isolated 3-hydroxyflavones under conventional and modified AFO conditions
Entry
Chalcone
Yield [%] under
conventional conditionsA
AdditiveB
Yield [%] under
modified conditions
1
2a
2b
2c
2d
2e
2f
38
45
28
19
0
BnPPh3Cl
C
70
C
2
–
–
3
BnPPh3Cl
BnPPh3Cl
BnPPh3Cl
BnPPh3Cl
BnPPh3Cl
EtPPh3I
55
4
49
32 (14)D
5
6
0
16
7
2g
2g
2d
2d
2d
2d
2d
2d
0
19
8
–
0
9
19
–
(n-Bu)4NBr
(n-Bu)4NI
(n-Bu)4NHSO4
i-PrPPh3I
67
10
11
12
13
14
67
–
62
–
63
–
n-PrPPh3Br
EtPPh3I
71
–
82
A5 % aqueous NaOH (12 equiv.), 30 % aqueous H2O2 (12 equiv.), ethanol/dioxane (1 : 1), room temperature, 48 h.
B5 % aqueous NaOH (12 equiv.), 30 % aqueous H2O2 (12 equiv.), PTC (0.1 equiv.), ethanol/dioxane (1 : 1), room temperature,
24–48 h.
CReaction was not undertaken.
D5 % aqueous NaOH (6 equiv.), 30 % aqueous H2O2 (6 equiv.), ethanol/dioxane (1 : 1), room temperature, 48 h.
series of compounds employed the conventional two-step
approach: generation of the requisite chalcones 2a–g via the
Claisen–Schmidt reaction, and subsequent oxidative cyclization
with basic peroxide (Scheme 2). In the event, the chalcones 2a–g
were obtained from the acetophenone 4 and aldehydes 5a–g in
moderate-to-good yields using potassium hydroxide in a mixed
solvent system of water/ethanol/dioxane over 3 days at room
temperature. The resultant chalcones were then subjected to
conventional AFO conditions (hydrogen peroxide and sodium
hydroxide) in the same solvent mixture of ethanol, dioxane, and
water for 48 h at room temperature. A complex reaction mixture
was obtained and only the desired 3-hydroxyflavones 3a–d were
obtained in pure form after acidification of the reaction mixture,
filtration, and recrystallization of the resultant solid (Table 1,
entries 1–4).
low yields of the 3,4-methylenedioxy and 3,5-dimethoxy com-
pounds (1c and 1d, respectively) could be isolated. Furthermore,
the 3-hydroxyflavones derived from the m-methoxy-substituted
chalcone 2e or from chalcones bearing electron withdrawing
groups (2f and 2g) could not be isolated under these conditions.
We hypothesized that key reaction intermediates, and in partic-
ular the dihydroflavanols 3, were precipitating from solution
in reactions that were low yielding or that had failed, therefore
negatively impacting the reaction outcome. Increasing the
reaction temperature, extending the reaction time, or changing
the solvent mixture to DMF/water did not improve the reaction
outcome (data not shown). Given the heterogeneous nature of
the reaction mixture, we wondered whether the addition of a
phase transfer catalyst may provide an alternative approach to
addressing substrate and intermediate solubility.[44] Preliminary
studies compared the effects of representative ammonium and
phosphonium phase transfer catalysts (tetrabutylammonium
While the p-methyl and p-methoxy hydroxyflavones (1a
and 1b, respectively) were obtained in acceptable yields, only

1104
D. Nhu, B. C. Hawkins, and C. J. Burns
bromide and benzyltriphenylphosphonium chloride) on the
AFO reaction of 2e, and though the former resulted in a complex
mixture of products as assessed by proton NMR, we found that
addition of benzyltriphenylphosphonium chloride led to smooth
conversion to the product 1e. Indeed, this catalyst significantly
improved the product yields in all cases explored (Table 1,
entries 1, 3–7), particularly when a large excess of peroxide and
base were employed (see entry 5). To further explore the effect
of phase transfer catalysis on the reaction, we surveyed the
effects of a range of commercially available phase transfer
catalysts (both ammonium and phosphonium salts) on the
reaction of the 3,5-dimethoxy chalcone (2d) (entries 9–14).
All catalysts trialled gave improved yields of the desired
product 1d, with ethyltriphenylphosphonium iodide affording
the product in 82 % yield. Surprisingly, however, the use of
ethyltriphenylphosphonium iodide as the catalyst for the AFO
reaction of 2g did not lead to any isolable quantities of the
3-hydroxyflavone 1g (entry 8).
The phase transfer catalysts employed presumably improve
the solubility of key reaction intermediates (such as the dihy-
droflavanols 3) allowing the reaction to proceed to completion.
Thus, though both ammonium and phosphonium salts smoothly
affect the formation of 1d, TLC and NMR analysis of the crude
reaction mixture of 2e and 2f under the conventional AFO
conditions indicated the presence of a complex mixture, of
which only a trace amount of the product was detectable
(Table 1, entries 5 and 6) along with unreacted starting material
and dihydroflavanols 3e and 3f (respectively). Similarly, when
2f was subjected to recently reported modified AFO condi-
tions,[41] minimal product could be observed. However, analysis
of the crude reaction mixture of these substrates in the presence
of benzyltriphenylphosphonium chloride showed complete con-
sumption of the chalcones, a small amount of the corresponding
intermediate 3 (removed during purification), and the desired
products 1e and 1f, isolated by recrystallization in 32 % and
16 % yields, respectively.
We are not aware of any reports on the use of phase transfer
catalysis for the AFO reaction despite the operational simplicity
of this modification. Phase transfer catalysis has been
previously employed with aqueous hydrogen peroxide in the
oxidation of alcohols though in these cases the reaction is
performed in the presence of metal catalysts such as tungsten
polyoxometallates.[45]
These modified conditions described, however, do not
overcome some known shortcomings of the AFO reaction.
Thus, for example, chalcones derived from aliphatic aldehydes
do not generate the corresponding 3-hydroxyflavones, and
2-hydroxy-6-methoxy-substituted chalcones also fail to react.
Moreover, the use of the ethyltriphenylphosphonium iodide did
not lead to formation of the 3-hydroxyflavone 1g despite this
being the best catalyst for the conversion of the chalcone 2d,
whereas benzyltriphenylphosphonium chloride led to formation
of flavone 1g, albeit in modest 16 % yield. This outcome may
reflect a level of substrate dependence on the reaction.
Experimental
Reagents were purchased from commercial suppliers and were
used without further purification. Infrared (IR) spectra were
obtained on a Bruker Tensor27 FT-IR spectrometer and the
frequencies were quoted in wavenumbers (cmꢀ1). NMR spectra
were recorded on a Bruker Advance DRX 300 (1H NMR at
300 MHz; 13C NMR at 75 MHz) and a Varian INOVA 600
(1H NMR at 600 MHz; 13C at 150 MHz). Melting points were
determined on the MPA100 Optimelt automated melting point
system and are uncorrected. Electrospray ionization (ESI) was
employed in mass spectrometry in tandem with reversed phase
liquid chromatography (LCMS) which was performed using two
methods. Method A: Finnigan LCQ Advantage MAX (column:
Gemini 3 mm C18 20 ꢁ 4.0 mm 110A column); solvent A: water
0.1 % formic acid; solvent B: acetonitrile 0.1 % formic acid;
gradient: 10–100 % B over 10 min; and detection: 100–600 nm
and ESI in positive mode with source temperature 3008C.
Method B: Waters ZQ 3100 (Column: XBridgeTM C18 5 mm
4.6 ꢁ 100 mm); solvent A: water 0.1 % formic acid; solvent B:
acetonitrile 0.1 % formic acid; gradient: 10–100 % B over
10 min; and detection: 100–600 nm and ESI positive ion mode,
single-quadrupole at 1508C. The purity of the compounds
was determined to be $98 % by HPLC at l ¼ 254 nm. High-
resolution mass spectrometry (HRMS) patterns were recorded
on a Bruker microTOFQ (University of Otago, New Zealand) or
on Agilent Q-TOF 6200 (Monash Institute of Pharmaceutical
Sciences, Melbourne, Australia) using an ESI source in either
the positive or negative modes.
1-(4-(Benzyloxy)-2-hydroxyphenyl)ethanone (4)
To
a solution of 1-(2,4-dihydroxyphenyl)ethanone (6 g,
39.4 mmol, 1 equiv.) in toluene (78.8 mL) were added potassium
acetate (6.97 g, 70.9 mmol, 1.8 equiv.), tetra-n-butylammonium
iodide [(n-Bu)4NI] (1.45 g, 3.94 mmol, 0.1 equiv.), and benzyl
bromide (4.65 mL, 47.3 mmol, 1.2 equiv.), and the reaction
mixture was heated to 60–808C for 6 h. Ice-cold water (200 mL)
was added to the cooled reaction mixture and acidified with 1 M
HCl to pH 1. The mixture was diluted with diethyl ether (Et2O;
200 mL) and the organic layer was collected. The aqueous layer
was extracted again with Et2O (100 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concen-
trated. The solid residue was purified by recrystallization from
a mixture of cyclohexane/ethyl acetate (EtOAc)/Et2O to
furnish the desired product as an off-white solid (6.7 g, 70 %),
mp 110–1158C. nmax (film)/cmꢀ1 3032, 1619, 1325. dH ( CDCl3,
300 MHz) 7.6 (1H, d, J 9.3, ArH), 7.44 – 7.32 (5H, m, ArH), 6.52
(2H, dd, J 8.2, 2.0, ArH), 6.51 (1H, s, ArH), 5.10 (2H, s,
OCH2Ph), 2.56 (3H, s, (CO)CH3). dC ( CDCl3, 75 MHz) 202.6,
165.2, 135.9, 132.4, 128.7, 128.3, 127.5, 114.1, 108.1, 101.9,
70.2, 26.2. Method A: tR 5.74. m/z (ESIþ) 243 ([MþH]þ). m/z
243.1002. HRMS Anal. Calc. for (C15H15O3) 243.1021.
General Procedure for the Synthesis of Chalcones
(Modified from Ref. 14)
To a suspension of 1-(4-(benzyloxy)-2-hydroxyphenyl)etha-
none (4) and aldehyde 5 (1 equiv.) in ethanol (EtOH)/dioxane
(1 : 1) (0.25 M) was added dropwise 40 % KOH aqueous solu-
tion (6 equiv.) while cooling on ice. The resulting blue–green
reaction mixture was then warmed to room temperature, and
stirring continued for 3 days. After this time, the solution was
cooled to 08C and acidified with 2 M acetic acid to pH 6. The
solid thus formed was collected by filtration or centrifugation
Conclusion
We have identified an operationally simple modification to the
AFO reaction providing access to a variety of 3-hydroxy-
flavones in significantly higher yields than those obtained from
the conventional reaction conditions. The phase transfer catal-
ysis presumably improves the solubility of key reaction inter-
mediates allowing the reaction to proceed to completion.

Phase Transfer Catalysis in the AFO Reaction
1105
(2 min at 1000g; repeated once after removal of the mother
liquor and addition of cold EtOH), washed with cold EtOH, and
recrystallized from a mixture of dichloromethane/cyclohexane.
The mother liquor was extracted with dichloromethane and
concentrated, and the resultant yellow solid was recrystallized
from the same solvent mixture or triturated with Et2O to give the
corresponding chalcones.
991, 935, 926, 836, 802. dH (CDCl3, 600 MHz) 13.39 (1H, s,
OH), 7.82 (1H, d, J 8.6, ArH), 7.79 (1H, d, J 15.4 Hz,
–CH¼CH–), 7.51 (1H, d, J 15.4, –CH¼CH–), 7.41 (5H, dt,
J 12.7, 7.4, ArH), 7.34 (1H, t, J 7.0, ArH), 5.11 (2H, s, OCH2Ph),
3.84 (6H, s, 2(OCH3)). dC (CDCl3, 150 MHz) 191.8, 166.6,
165.3, 161.1, 144.5, 136.6, 135.8, 131.3, 128.7, 128.3, 127.6,
120.8, 114.2, 108.3, 106.4, 102.8, 102.1, 70.3, 55.5, 55.5.
Method A: tR 6.41. m/z (ESIþ) 391.2 ([MþH]þ). m/z (HRMS
ESIþ) 413.1370, 391.1516 ([MþH]þ); [MþNa]þ requires
413.1365.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-
(4-methoxyphenyl)prop-2-en-1-one (2a)
The title compound[46] was obtained as yellow needles
(981 mg, 35 %), mp: 132–1358C. nmax (film)/cmꢀ1 3001,
2936, 1636, 1574, 1505, 1455, 1275, 1251, 1152, 1131, 836,
802, 737, 697. dH (CDCl3, 300 MHz) 7.89 (1H, d, J 18.0,
–CH¼CH–), 7.87 (1H, d, J 9.0, ArH), 7.64 (2H, d, J 8.8,
ArH), 7.52–7.33 (6H, m, ArH, –CH¼CH–, overlap), 6.97 (2H,
d, J 8.8, ArH), 6.62–6.56 (2H, m, ArH), 5.14 (1H, s, OCH2Ph),
3.89 (2H, s, OCH3). dC (CDCl3, 75 MHz) 191.9, 166.5, 165.1,
161.8, 144.3, 135.9, 131.2, 130.4, 128.7, 128.3, 127.5, 117.9,
114.5, 114.4, 108.1, 102.1, 70.3, 55.4. Method A: tR 6.32. m/z
(ESIþ) 361.3 ([MþH]þ). m/z 383.1254. HRMS Anal. Calc. for
(C23H20O4Na) 383.1259.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-
(3-methoxyphenyl)prop-2-en-1-one (2e)
The title compound[47] was obtained as yellow solid (713 mg,
39 %), mp 137–1398C. nmax (film)/cmꢀ1 3060, 3037, 2940,
1640, 1574, 1495, 1456, 1362, 1304, 1258, 1213, 1190, 1156,
978, 956, 853, 738, 698. dH (CDCl3, 300 MHz) 13.39 (1H, s,
OH), 7.86 (1H, d, J 15, –CH¼CH–), 7.84 (1H, d, J 9.4, ArH),
7.56 (1H, d, J 15.5, –CH¼CH–), 7.45–7.36 (5H, m, ArH), 7.34
(1H, d, J 9, ArH), 7.24 (1H, m, ArH), 7.16 (1H, m, ArH), 6.98
(1H, ddd, J 8.1, 2.6, 1.0, ArH), 6.59–6.55 (2H, m, ArH), 5.12
(2H, s, OCH2Ph), 3.87 (3H, s, OCH3). dC (CDCl3, 75 MHz)
191.8, 166.6, 165.4, 160.0, 144.4, 136.2, 135.9, 131.3, 130.0,
128.7, 128.3, 127.6, 121.2, 120.6, 116.4, 114.3, 113.6, 108.3,
102.1, 70.3, 55.4. Method A: tR 6.34. m/z (ESIþ) 361.1
([MþH]þ). m/z 383.1228. HRMS Anal. Calc. for (C23H20O4Na)
383.1259.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-p-tolylprop-
2-en-1-one (2b)
The title compound was obtained as a yellow solid (225 mg,
45 %), mp 117–1208C. nmax (film)/cmꢀ1 2938, 2837, 1685,
1598, 1556, 1515, 1252, 1135, 1112, 1031, 1006, 898, 830. dH
(CDCl3, 600 MHz) 13.48 (1H, s, br, OH), 7.87 (1H, -d, J 15.4,
CH¼CH–), 7.84 (1H, d, J 9.3, ArH), 7.54 (d, J 7.8, ArH,
overlap), 7.53 (1H, d, J 15.0, –CH¼CH–, overlap), 7.41 (5H,
dt, J 12.9, 7.4, ArH), 7.37–7.32 (1H, m, ArH), 7.23 (2H, d, J 8.0,
ArH), 6.61–6.37 (2H, m, ArH), 5.10 (2H, s, OCH2Ph), 2.39 (3H,
s, PhCH3). dC (CDCl3, 151 MHz) 191.9, 166.6, 165.2, 144.6,
141.3, 135.9, 132.0, 131.3, 129.7, 128.7, 128.6, 128.3, 127.6,
119.2, 114.3, 108.2, 102.1, 70.2, 21.6. Method A: tR 6.55.
m/z (ESIþ) 345.4 ([MþH]þ). m/z (HRMS ESIþ) 367.1221;
[MþNa]þ requires 367.1310.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-
(4-bromophenyl)prop-2-en-1-one (2f)
The title compound was prepared according to the general
procedure as an off-white solid (480 mg, 29 %), mp 148–1518C.
n
max (film)/cmꢀ1 3031, 1648, 1575, 1514, 1489, 828, 790, 670,
635. dH (CDCl3, 300 MHz) 7.83 (1H, d, J 15.0, –CH¼CH–,
overlap), 7.83 (1H, d, J 6.0, ArH, overlap), 7.61–7.52 (5H, m,
ArH), 7.52–7.37 (5H, m, ArH, –CH¼CH–), 6.61–6.57 (2H, m,
ArH), 5.14 (2H, s, OCH2Ph). dC (CDCl3, 75 MHz) 191.5, 166.7,
165.5, 143.0, 135.8, 133.7, 132.3, 131.3, 129.9, 128.7, 128.4,
127.6, 125.0, 120.9, 114.2, 108.4, 102.1, 70.3. Method A: tR
6.59. m/z (ESIþ) 407.2, 409.2 ([MþH]þ). m/z (HRMS ESIþ)
431.0253 and 433.0234; [MþNa]þ requires 431.0259 and
433.0238.
(E)-3-(Benzo[d][1,3]dioxol-5-yl)-1-(4-(benzyloxy)-2-
hydroxyphenyl)prop-2-en-1-one (2c)
The title compound was obtained from the general procedure
as a yellow solid (1.05 g, 56 %), mp 175–1788C. nmax (film)/
cmꢀ1 2914, 1635, 1603, 1560, 1505, 1478, 1371, 1241, 1212,
1032, 1005, 840, 808, 790, 670. dH (CDCl3, 300 MHz) 7.83
(1H, d, J 15.9, –CH¼CH–), 7.82 (1H, d, J 6.7, ArH), 7.48–7.34
(6H, m, ArH, –CH¼CH–, overlap), 7.20–7.14 (2H, m, ArH),
6.88 (1H, d, J 8.0, ArH), 6.61–6.55 (2H, m, ArH), 6.06 (2H, s,
OCH2O), 5.14 (2H, s, OCH2Ph). dC (CDCl3, 75 MHz) 191.8,
166.6, 165.2, 150.1, 148.5, 144.3, 135.9, 131.2, 129.3, 128.7,
128.3, 127.6, 125.4, 118.3, 114.3, 108.7, 108.2, 106.7, 102.1,
101.7, 70.3. Method B: tR 9.05. m/z (ESIþ) 375.1 ([MþH]þ). m/z
397.1030, 375.1220. HRMS Anal. Calc. for (C23H18O5Na)
397.1052, (C23H19O5) 375.1232.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-(4-
(trifluoromethoxy)phenyl)prop-2-en-1-one (2g)
The title compound[46] was prepared according to the general
procedure as a yellow solid (640 mg, 22 %), mp 120–1258C.
nmax (film)/cmꢀ1 3040, 1643, 1608, 1573, 1508, 1261, 1212,
1179, 1154, 1020, 976, 731, 692, 659. dH (CDCl3, 300 MHz)
13.35 (1H, s), 7.86 (1H, d, J 15.0, –CH¼CH–), 7.4 (1H, d, J 9.0,
ArH), 7.69 (1H, d, J 8.3, ArH), 7.56 (1H, d, J 15.5, –CH¼CH–),
7.47–7.33 (5H, m, ArH), 7.29 (2H, d, J 7.9, ArH), 6.63–6.56
(2H, m, ArH), 5.13 (1H, s, OCH2Ph). dC (CDCl3, 75 MHz)
191.5, 166.7, 165.5, 150.7, 142.6, 135.8, 133.4, 131.3, 129.9,
128.7, 128.4, 127.6, 122.1, 121.2, 118.7, 114.2, 108.4, 102.2,
70.3. Method A: tR 6.55. m/z (ESIꢀ) 413.2 ([MꢀH]ꢀ). m/z
415.1185. HRMS Anal. Calc. for (C23H18F3O4) 415.1157.
(E)-1-(4-(Benzyloxy)-2-hydroxyphenyl)-3-
(3,5-dimethoxyphenyl)prop-2-en-1-one (2d)
General Procedure for the Synthesis of 3-Hydroxyflavones
The title compound was obtained as a yellow solid after
workup (4.23 g, 43 %), mp 133–1378C. nmax (film)/cmꢀ1 3001,
2836, 2939, 1636, 1574, 1505, 1455, 1205, 1152, 1131, 1017,
To a solution of 1-(4-(benzyloxy)-2-hydroxyphenyl)ethanone
(4) and the appropriate aldehyde 5 (1 equiv.) in a mixture of

1106
D. Nhu, B. C. Hawkins, and C. J. Burns
EtOH/dioxane (1 : 1) (0.25 M) at 08C was added aqueous KOH
(40 %). The reaction mixture was stirred at room temperature for
2 days. The reaction was cooled to 08C, followed by dropwise
addition of 2 M acetic acid (AcOH) until the mixture became
slightly acidic (pH 4–5). The aqueous layer was extracted thrice
with dichloromethane. The combined organic layers were
washed with brine, concentrated, and dried (Na2SO4) to afford
the corresponding chalcone 2 as a yellow solid. The crude res-
idue was resuspended in the solvent mixture of EtOH/dioxane
(0.07 M) and cooled to 08C. An aqueous solution of NaOH (5 %)
(12 equiv.) was added to afford an orange solution. To this was
added dropwise an aqueous solution of H2O2 (30 %) (12 equiv.).
The appropriate phase transfer catalyst (benzyltriphenylpho-
sphonium chloride or as described in Table 1) (0.1 equiv.) was
added to the resultant yellow suspension and the reaction mix-
ture was allowed to warm to room temperature overnight to 48 h
and monitored by TLC. The reaction mixture was then acidified
with 1 M HCl while cooling on ice. The yellow solid was col-
lected by filtration or centrifugation (2 min at 1000g; repeated
once after removal of the mother liquor and addition of cold
EtOH) and recrystallized with dichloromethane/EtOH to
afford the 3-hydroxyflavone.
([MþH]þ). m/z (HRMS ESIꢀ) 387.0860; [M–H]ꢀ requires
387.0869.
7-(Benzyloxy)-2-(3,5-dimethoxyphenyl)-3-hydroxy-
4H-chromen-4-one (1c)
The title compound was obtained as a white solid (49 %), mp
235–2548C. nmax (film)/cmꢀ1 3255, 2916, 1610, 1568, 1455,
1404, 1254, 1206, 1185, 702, 746. dH (CDCl3, 300 MHz) 8.17
(1H, d, J 8.9, ArH), 7.53–7.35 (7H, m, ArH), 7.10 (1H, dd, J 8.9,
2.4, ArH), 7.06 (1H, d, J 2.3, ArH), 6.60 (1H, t, J 2.3, ArH), 5.21
(2H, s, –OCH2Ph), 3.91 (6H, s, OCH3). dC (CDCl3, 75 MHz)
172.8, 163.4, 160.8, 157.3, 138.2, 135.7, 132.8, 128.8, 128.5,
127.6, 126.9, 115.39, 114.7, 105.8, 102.2, 101.0, 77.4, 77.0,
76.6, 70.6, 55.5. Method A: tR 8.67. m/z (ESIþ) 405.3
([MþH]þ). m/z (HRMS ESIꢀ) 403.1136; [MꢀH]ꢀ requires
403.1182.
7-(Benzyloxy)-3-hydroxy-2-(3-methoxyphenyl)-
4H-chromen-4-one (1e)
The title compound was obtained as a yellow solid (32 %),
mp 249–2608C. nmax (film)/cmꢀ1 3256, 2916, 1611, 1568, 1504,
1455, 1254, 1206, 1185, 1046, 966, 765, 746. dH (CDCl3,
600 MHz) 8.14 (1H, d, J 8.9, ArH), 7.81 (1H, d, J 8.1, ArH),
7.79 (1H, s, br, ArH), 7.45 (3H, t, J 7.1, ArH), 7.42 (3H, t, J 8.0,
ArH), 7.37 (1H, t, J 7.2, ArH), 7.07 (1H, dd, J 8.9, 2.1, ArH),
7.04 (1H, d, J 2.0, ArH), 7.00 (1H, dd, J 8.3, 2.2, ArH), 5.18 (2H,
s, OCH2Ph), 3.88 (3H, d, J 15.8, OCH3). dC (DMSO, 75 MHz)
172.4, 162.7, 160.4, 156.3, 144.0, 139.1, 136.1, 133.0, 128.5,
128.1, 127.9, 126.2, 115.2, 115.1, 105.8, 101.4, 101.3, 70.1,
55.4. Method B: tR 6.07. m/z (ESIþ) 375.3 ([MþH]þ). m/z
(HRMS ESIþ) 397.1052; [MþNa]þ requires 397.1052.
7-(Benzyloxy)-3-hydroxy-2-(4-methoxyphenyl)-
4H-chromen-4-one (1a)
The title compound[48] was obtained as a yellow solid (70 %),
mp 247–2588C. nmax (film)/cmꢀ1 1650, 1451, 1404, 1255, 1180,
832, 747. dH (DMSO, 300 MHz) 8.43 (2H, d, J 7.6, ArH), 7.96
(1H, d, J 8.9, ArH), 7.56–7.23 (6H, m, ArH), 7.02 (3H, s, ArH),
5.26 (2H, s, OCH2Ph), 3.82 (3H, s, OCH3). dC (DMSO, 75 MHz)
161.9, 159.0, 155.9, 144.5, 140.8, 136.9, 129.09, 128.5, 128.3,
127.9, 126.6, 118.4, 116.2, 115.0, 114.3, 114.0, 101.4, 70.3,
55.6. Method A: tR 6.06. m/z (ESIþ) 375.3 ([MþH]þ). m/z
397.1017. HRMS Anal. Calc. for (C23H18O5Na) 397.1052.
7-(Benzyloxy)-2-(4-bromophenyl)-3-hydroxy-
4H-chromen-4-one (1f)
The title compound was obtained as an off-white solid
(16 %), mp 202–2048C. nmax (film)/cmꢀ1 3216, 1602, 1567,
1453, 1413, 1254, 1214, 832, 699, 750, 633. dH (DMSO,
300 MHz) 9.74 (1H, s, OH), 8.17 (2H, d, J 8.8, ArH), 8.02
(1H, d, J 8.9, ArH), 7.78 (2H, d, J 8.8, ArH), 7.53–7.48 (2H, m,
ArH), 7.47–7.33 (4H, m, ArH), 7.13 (1H, dd, J 8.9, 2.3, ArH),
5.28 (2H, s, OCH2Ph). dC (DMSO, 75 MHz) 172.8, 163.3, 156.8,
143.9, 139.6, 136.7, 132.1, 131.1, 129.7, 129.0, 128.6, 128.3,
126.8, 123.5, 115.8, 115.7, 101.8, 70.5. Method B: tR 9.35. m/z
(ESIþ) 421.1, 423.1 ([MþH]þ). m/z (HRMS ESIꢀ) 421.0081
and 423.0062; [MꢀH]ꢀ requires 421.0075 and 423.0055.
7-(Benzyloxy)-3-hydroxy-2-p-tolyl-4H-chromen-
4-one (1b)
The title compound was obtained as yellow needles (conven-
tional method, no PTC, 233 mg, 45 %), mp 216–2208C. nmax
(film)/cmꢀ1 3255, 2916, 1610, 1567, 1455, 1404, 1254, 1206,
1185. dH (CDCl3, 300 MHz) 8.18 (1H, d, J 9.0, ArH), 8.15 (2H,
d, J 8.4, ArH), 7.53–7.39 (5H, m, ArH), 7.36 (2H, d, J 8.2, ArH),
7.12–7.04 (2H, m, ArH), 5.21 (2H, s, OCH2Ph), 2.46 (3H, s,
PhCH3). dC (CDCl3, 150 MHz) 172.7, 163.0, 156.8, 145.2,
140.0, 138.9, 136.6, 129.5, 129.0, 128.9, 128.4, 127.8, 115.8,
115.7, 101.7, 101.6, 70.5, 21.5. Method B: tR 9.05. m/z (ESIþ)
359.1 ([MþH]þ). m/z (HRMS ESIꢀ) 357.1137; [MꢀH]ꢀ
requires 357.1127.
7-(Benzyloxy)-3-hydroxy-2-(4-(trifluoromethoxy)
phenyl)-4H-chromen-4-one (1g)
The title compound was obtained as a bright yellow solid
(19 %), mp 196–2008C. nmax (film)/cmꢀ1 2922, 1618, 1501,
1451, 1260, 1212, 1180, 847, 747. dH (DMSO, 300 MHz) 8.56
(2H, d, J 8.4, ArH), 7.97 (1H, d, J 8.9, ArH), 7.53–7.48 (2H, m,
ArH), 7.47–7.32 (5H, m, ArH), 7.29 (1H, d, J 2.2, ArH), 7.02
(1H, dd, J 8.9, 2.3, ArH), 5.26 (1H, s, OCH2Ph). dC (DMSO,
75 MHz) 170.3, 162.3, 156.3, 147.3, 142.6, 136.8, 129.0, 128.6,
128.3, 127.8, 126.8, 121.0, 116.1, 114.5, 101.4, 70.3. Method B:
tR 9.28. m/z (ESIþ) 429.2 ([MþH]þ). m/z (HRMS ESIþ)
429.0953; [MþH]þ requires 429.0950.
2-(Benzo[d][1,3]dioxol-5-yl)-7-(benzyloxy)-
3-hydroxy-4H-chromen-4-one (1d)
The title compound was obtained as a yellow solid (55 %),
mp 226–2298C. nmax (film)/cmꢀ1 3259, 1599, 1563, 1500, 1470,
1252, 1208, 1182, 1122, 1015, 997, 857, 818. dH (CDCl3,
300 MHz) 8.16 (1H, d, J 8.9, ArH), 7.84 (1H, dd, J 8.4, 1.8,
ArH), 7.76 (1H, d, J 1.7, ArH), 7.52–7.36 (5H, m, ArH), 7.10
(1H, dd, J 8.9, 2.4, ArH), 7.04 (1H, d, J 2.3, ArH), 6.99 (1H, d,
J 8.4, ArH), 6.08 (2H, s, –CH2O–), 5.21 (2H, s, OCH2Ph). dC
(CDCl3, 75 MHz) 172.5, 163.3, 157.1, 137.5, 135.7, 128.8,
128.5, 127.5, 126.8, 125.2, 122.6, 115.2, 114.8, 108.7, 107.9,
101.7, 101.0, 70.6. Method A tR 5.98. m/z (ESIþ) 389.0
Supplementary Material
1H NMR, 13C NMR and LCMS spectra of all compounds are
available on the Journal’s website.

Phase Transfer Catalysis in the AFO Reaction
1107
Acknowledgements
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Y. Me´ly, A. S. Klymchenko, Methods Appl. Fluoresc. 2013, 1, 025002.
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This work was supported by scholarships, fellowships, and grants from the
following: Victorian State Government Operational Infrastructure Support
(OIS) Grant, Australian Cancer Research Foundation, Cancer Therapeutics
CRC (DN), Dyson Bequest funding (CJB), and an Independent Research
Institutes Infrastructure SupportScheme Grant (361646) from the Australian
National Health and Medical Research Council. Prof. David Huang and
Assoc. Prof. Spencer Williams are thanked for useful discussions. Ms Dana
Buczek is acknowledged for analytical support.
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