Reactions of carbanions with 1,3-benzodioxin-4-ones: Facile routes to flavones, aurones, and acyl phloroglucinols

Article abstract of DOI:10.1055/s-2008-1078597

Two 1,3-benzodioxin-4-ones react with enolates, acetylides and aryllithium reagents to afford adducts that were converted into flavones, aurones, and an acyl phloroglucinol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078597

PAPER
2427
Reactions of Carbanions with 1,3-Benzodioxin-4-ones: Facile Routes to
Flavones, Aurones, and Acyl Phloroglucinols
R
eactions of Carba
e
nions with
o
1,3-Benzodi
r
oxin-4-o
g
nes e A. Kraus,* Jingqiang Wie, Aniket Thite
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +1(515)2940105; E-mail: gakraus@iastate.edu
Received 22 February 2008; revised 28 April 2008
Treatment of 2 with the lithium anion of phenylacetylene
at 0 °C (generated from phenylacetylene and n-butyllithi-
um at –78 °C) afforded the acetylenic ketone 6 in 45%
yield. Similarly, the anion of 3,4-dimethoxyphenylacety-
lene furnished the ketone 7 in 31% isolated yield. When
3,4-dimethoxybromobenzene was metalated with n-butyl-
lithium in THF at –78 °C and reacted with 3, adduct 8 was
produced in 74% yield. When 4-benzyloxy-3-methoxy-
bromobenzene was lithiated and reacted with 2, ben-
zophenone 9 was generated in 70% yield. The reaction of
phenyllithium with 2 produced adduct 10 in 75% yield
whose spectra matched the literature data.5
Abstract: Two 1,3-benzodioxin-4-ones react with enolates, acetyl-
ides and aryllithium reagents to afford adducts that were converted
into flavones, aurones, and an acyl phloroglucinol.
Key words: carbanions, ketones, natural products, nucleophilic ad-
dition
The carbanion addition chemistry of 1,3-benzodioxin-4-
ones has been little studied. To the best of our knowledge,
only two reactions of 1,3-benzodioxin-4-ones with a car-
banion have been reported. In one case an organozinc re-
agent reacted with a 1,3-benzodioxin-4-one to afford a
tertiary alcohol and in the other case a Grignard reagent
reacted to provide a ketone.1,2 The infrequent use of 1,3-
benzodioxin-4-ones was in part due to the absence of a
convenient general method of preparation.3 Recently,
Takahashi reported an improved synthesis of 1,3-benzo-
dioxin-4-ones such as 1.4 Methylation of 1 using potassi-
um carbonate and methyl iodide afforded 2 in 100% yield.
Protection of 1 using benzenesulfonyl chloride and trieth-
ylamine gave 3 in 98% yield (Scheme 1).
We next studied the conversion of adducts from Table 1
into natural products. Diketone 4 was readily cyclized us-
ing PTSA and then deprotected using potassium carbon-
ate in methanol to afford the natural product chrysin (11)
in 69% overall yield from acetophenone (Scheme 2). The
1H and 13C NMR spectra of our synthetic material were
identical with the spectra obtained from an authentic sam-
ple of chrysin.6 The b-diketone 5 could be cyclized using
PTSA and deprotected to provide apigenin (12) in 42%
1
overall yield from 5. Again, H and 13C NMR spectra of
Because of the ready availability of 2 and 3, we evaluated
their reactions against a panel of carbanions. These reac-
tions are depicted below in Table 1. The reaction of the
enolate of acetophenone [prepared by deprotonation of
acetophenone with lithium diisopropylamide (LDA) in
THF at –78 °C] with 2 did not take place and only the
starting materials were recovered. However, the reaction
of the enolate with the more electrophilic reagent 3 gener-
ated b-diketone 4 in 77% yield. Unexpectedly, no reaction
of the enolate of 4-methoxyacetophenone with 3 took
place and only the starting materials were recovered. For-
tunately, the LDA-derived enolate of 4-benzenesulfonyl-
oxyacetophenone reacted efficiently with 3 to produce the
b-diketone 5 in 66% yield.
our synthetic material matched the spectra of an authentic
sample of apigenin.6 Apigenin is a natural antioxidant that
occurs in a number of species of Hypericum.7 It has been
shown to promote cell cycle arrest and apoptosis in vari-
ous malignant cell lines and is also a potent inhibitor of
glucosyltransferase activity.8
Ketone 6 was rapidly cyclized to aurone 13 upon reaction
with potassium carbonate in boiling acetone. The exclu-
sive 5-exo reaction pathway has precedent in the work of
Garcia.9 The NMR spectrum of our material is identical to
that of the natural product. The melting point of 13 com-
pares closely with the literature value.10 Similarly, adduct
7 was converted into aurone 14 in 80% yield (Scheme 3).
The 1H NMR spectrum of 14 matched the literature data.11
HO
O
Me
Me
MeO
O
O
Me
Me
BsO
O
Me
Me
MeI
K2CO3
BsCl
Et3N
O
O
O
98%
100%
OH
O
OMe
OBs
O
2
1
3
Scheme 1
SYNTHESIS 2008, No. 15, pp 2427–2431
x
x.
x
x
.
2
0
0
8
Advanced online publication: 17.07.2008
DOI: 10.1055/s-2008-1078597; Art ID: M01008SS
© Georg Thieme Verlag Stuttgart · New York

2428
G. A. Kraus et al.
PAPER
Table 1 The Reactions of Carbanions with 1,3-Benzodioxin-4-ones 2 and 3
R'O
O
O
Me
Me
R'O
OH
O
RLi
+
O
R
OR'
OR'
RLi
Conditionsa
Acceptor
Yield (%)
Acetophenone enolate
Acetophenone enolate
A
A
A
A
B
B
B
B
2
3
3
3
2
2
3
2
2
0
77
0
–
4
4-Methoxyacetophenone enolate
4-Benzenesulfonyloxyacetophenone enolate
Lithium phenylacetylide
–
60
45
31
74
70
75
5
6
Lithium 3,4-dimethoxyphenylacetylide
3,4-Dimethoxyphenyllithiumb
4-Benzyloxy-3-methoxyphenyllithiumb
Phenyllithiumb
7
8
9
10
a Ketone, LDA, –78 °C.
b Aryl bromide, n-BuLi, –78 °C.
X
BsO
OH
HO
1. PTSA
HO
O
O
X
2. K2CO3
MeOH
H
OBs
O
OH
4: X = H
5: X = OBs
11: X = H
12: X = OH
Scheme 2
R
R
R
MeO
O
R
K2CO3
MeO
OH
O
O
OMe
OMe
6: R = H
7: R = OMe
13: R = H
14: R = OMe
Scheme 3
Acyl phloroglucinols are a diverse class of natural prod- in good yields. The adducts could be converted into the
ucts that exhibit antibacterial activity, anticancer activity flavones chrysin and apigenin, aurones, and an acyl phlo-
and antitubercular activity.12 Removal of the benzyl pro- roglucinol.
tecting group from ketone 9 using hydrogen and 10% pal-
ladium on carbon afforded the acyl phloroglucinol 15 in
73% yield (Scheme 4). The identity of synthetic ben-
MeO
OMe
O
MeO
OMe
1
zophenone 15 was confirmed by comparison of our H
OBn
OH
OMe
NMR, 13C NMR, LRMS, and HRMS data with the pub-
lished spectra for the natural product.13 This is the first
synthesis of benzophenone 15.
Pd/C
H2
OH
OMe
OH
O
9
15
In summary, 1,3-benzodioxin-4-ones 2 and 3 react with a
number of commonly used carbanions to provide adducts
Scheme 4
Synthesis 2008, No. 15, 2427–2431 © Thieme Stuttgart · New York

PAPER
Reactions of Carbanions with 1,3-Benzodioxin-4-ones
2429
1H NMR (300 MHz, CDCl3): d = 6.50 (d, J = 2.4 Hz, 1 H), 6.55 (d,
J = 2.4 Hz, 1 H), 6.95 (s, 1 H), 7.39–7.51 (m, 4 H), 7.55–7.72 (m, 6
H), 7.87–7.91 (m, 4 H), 11.82 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 98.7, 109.2, 111.0, 114.1, 127.4,
128.7, 128.9, 129.2, 129.5, 129.7, 133.2, 133.3, 134.3, 135.0, 135.1,
135.2, 149.0, 153.0, 163.3, 179.5, 191.8.
Tetrahydrofuran was distilled from sodium benzophenone ketyl.
Dichloromethane, toluene and HMPA were distilled over calcium
hydride. All experiments were performed under argon atmosphere.
Organic extracts were dreid over anhydrous sodium sulfate. Infra-
red spectra were obtained on a Perkin-Elmer model 1320 spectro-
photometer. Nuclear magnetic resonance experiments were
performed with either a Varian 300 MHz or a Bruker 400 MHz in-
strument. High-resolution mass spectra were recorded on a Kratos
model MS-50 spectrometer and low-resolution mass spectra were
performed with a Finnegan 4023 mass spectrometer. Standard grade
silica gel (60 Å) was used for flash column chromatography.
MS: m/z = 552, 470, 419, 394, 393, 103, 77.
HRMS: m/z calcd for C27H20O9S2: 552.0549; found: 552.0555.
1-(2,4-Dibenzenesulfonyloxy-6-hydroxyphenyl)-3-(4-benzene-
sulfonyloxyphenyl)propane-1,3-dione (5)
5,7-Dimethoxy-2,2-dimethylbenzo[1,3]dioxin-4-one (2)
To 1 (0.30 g, 1.4 mmol) and anhyd K2CO3 (1.18 g, 8.57 mmol) in
acetone (40 mL) at 0 °C was slowly added MeI (1.22 g, 8.57 mmol).
The mixture was warmed slowly to r.t., poured into H2O (20 mL),
and extracted with EtOAc (2 × 20 mL). The combined organic lay-
ers were washed with brine (10 mL) and dried (MgSO4). Evapora-
tion of the solvent and purification of the residue by flash
chromatography (hexanes–EtOAc, 2:1) afforded compound 2 (0.34
g, ~100%) as a light yellow solid; mp 128–129 °C; Rf = 0.38
(EtOAc–hexanes, 1:1).
Compound 5 was taken on directly to 12 without purification.
1-(2,4-Dimethoxy-6-hydroxyphenyl)-3-phenylprop-2-ynone (6)
To phenylacetylene (20 mg, 0.2 mmol) in THF (5 mL ) at 0 °C was
added n-BuLi (2.5 M, 80 mL, 0.2 mmol) slowly. After 1 h at 0 °C,
the lithium reagent was cooled to –78 °C, and compound 2 (43 mg,
0.18 mmol) in THF (2 mL) of was added slowly. The mixture was
warmed slowly to r.t. and stirred for 2 h. The mixture was neutral-
ized with 0.5 M aq AcOH, diluted with H2O (20 mL) and extracted
with EtOAc (2 × 20 mL). The organic layers were washed with
brine (10 mL) and dried (MgSO4). Evaporation of the solvent and
purification of the residue by flash chromatography twice (hex-
anes–EtOAc, 2:1 and hexanes–CH2Cl2, 1:2) afforded the starting
material 2 (19 mg) and product (23 mg, 45% yield, 82% conver-
sion); Rf = 0.24 (CH2Cl2–hexanes, 2:1).
1H NMR (300 MHz, CDCl3): d = 3.85 (s, 3 H), 3.93 (s, 3 H), 5.94
(d, J = 2.4 Hz, 1 H), 6.07 (d, J = 2.4 Hz, 1 H), 7.42 (m, 3 H), 7.63
(m, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.9, 56.0, 89.9, 91.3, 93.7, 95.1,
107.3, 121.4, 128.8, 130.7, 133.2, 162.9, 167.6, 168.5, 177.8.
1H NMR (300 MHz, CDCl3): d = 1.68 (s, 6 H), 3.83 (s, 3 H), 3.91
(s, 3 H), 6.06 (d, J = 3 Hz, 1 H), 6.13 (d, J = 3 Hz, 1 H).
5,7-Dibenzenesulfonyloxy-2,2-dimethylbenzo[1,3]dioxin-4-one
(3)
To 1 (0.240 g, 1.14 mmol) in THF (20 mL) at 0 °C was added Et3N
(0.25 g, 2.5 mmol), followed by slow addition of benzenesulfonyl
chloride (0.44 g, 2.5 mmol). The mixture was warmed slowly to r.t.
and stirred overnight. The solution was neutralized with 0.5 M aq
AcOH, diluted with H2O (20 mL) and extracted with EtOAc (2 × 20
mL). The combined organic layers were washed with brine (10 mL)
and dried (MgSO4). Evaporation of the solvent and purification of
the residue by flash chromatography (hexanes–EtOAc, 2:1) afford-
ed compound 3 (0.55 g, 98%) as a white solid; mp 132–133 °C;
Rf = 0.18 (EtOAc–hexanes, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.61 (s, 6 H), 6.68 (d, J = 2.4 Hz,
1 H), 6.75 (d, J = 2.4 Hz, 1 H), 7.52–7.63 (m, 4 H), 7.66–7.77 (m, 2
H), 7.87–7.90 (m, 2 H), 9.95–7.98 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 25.6, 106.8, 107.4, 110.6, 112.7,
128.6, 129.2, 129.4, 129.9, 134.8, 135.0, 135.3, 149.7, 154.4, 156.0,
158.1.
1-(2,4-Dimethoxy-6-hydroxyphenyl)-3-(3,4-dimethoxyphe-
nyl)prop-2-ynone (7)
To a solution of 3,4-dimethoxyphenylacetylene (200 mg, 1.24
mmol) in THF (10 mL) at 0 °C was added n-BuLi (2.5 M solution
in hexanes, 0.5 mL, 1.24 mmol). After 1 h at 0 °C, the solution was
cooled further to –78 °C and 2 (150 mg, 0.62 mmol) in THF (5 mL)
was added dropwise. The mixture was gradually warmed to r.t. and
stirred overnight upon which it was quenched with aq 4.3 N AcOH.
The resulting solution was diluted with EtOAc and the EtOAc layer
was washed with H2O (20 mL) and brine (10 mL) successively. The
organic layer was dried (MgSO4), filtered, and evaporated in vacuo.
The residue was purified twice by flash column chromatography on
silica gel (hexanes–EtOAc, 6:1 and CH2Cl2–EtOAc, 19:1) to afford
the acetylenic ketone 7 (66 mg, 31%).
MS: m/z = 490, 489, 432, 431, 141, 140.
HRMS: m/z calcd for C22H18O9S2: 490.0392; found: 490.0398.
1H NMR (400 MHz, CDCl3): d = 7.28–7.27 (m, 1 H), 7.14 (s, 1 H),
6.89 (d, J = 8.4 Hz, 1 H), 6.09 (d, J = 2.4 Hz, 1 H), 5.96 (d, J = 2.0
Hz, 1 H), 3.95 (s, 3 H), 3.94 (s, 3 H), 3.92 (s, 3 H), 3.86 (s, 3 H).
Reaction of Ketones with 3 General Procedure
To i-Pr2NH (1 equiv) in THF (0.2 M) at –78 °C was added n-BuLi
(1 equiv) slowly. After 5 min, the temperature was raised to 0 °C for
15 min. After the solution was cooled to –78 °C, the respective ke-
tone (1 equiv) in THF (5 mL/mmol) was added slowly. After stir-
ring at –78 °C for 1 h, compound 3 (0.5 equiv) in THF (2 mL/mmol)
was added slowly. The mixture was warmed slowly to r.t. and
stirred for 2 h. The mixture was neutralized with 0.5 M aq AcOH,
diluted with H2O (20 mL), and extracted with EtOAc (2 × 20 mL).
The organic layers were washed with brine (20 mL) and dried
(MgSO4). Evaporation of the solvent and purification of the residue
by flash chromatography (hexanes–EtOAc, 2:1) afforded the puri-
fied product (Table 1).
Reaction of Aryllithium Reagents with 2 or 3; General Proce-
dure
To aryl bromide (1.0 equiv) in THF (5 mL/mmol) at –78 °C was
added n-BuLi (0.95 equiv) dropwise. After 30 min at –78 °C, the
temperature was increased to 0 °C for 1 h and the mixture was
cooled to –78 °C. Compound 2 or 3 (0.3 equiv, see Table 1) in 5
mL/mmol of THF was added slowly at –78 °C. The mixture was
warmed slowly to r.t. and stirred overnight. The solution was neu-
tralized by 0.5 M aq HCl, diluted with H2O (20 mL) and EtOAc
(2 × 20 mL). The combined organic layers were washed with brine
(10 mL) and dried (MgSO4). Evaporation of the solvent and purifi-
cation of the residue by flash chromatography (hexanes–
EtOAc, 2:1) afforded the purified product.
1-(2,4-Dibenzenesulfonyloxy-6-hydroxyphenyl)-3-phenylpro-
pane-1,3-dione (4)
Rf = 0.38 (EtOAc–hexanes, 1:2).
Synthesis 2008, No. 15, 2427–2431 © Thieme Stuttgart · New York

2430
G. A. Kraus et al.
PAPER
(2,4-Dibenzenesulfonyloxy-6-hydroxyphenyl)(3,4-dimethoxy-
phenyl)methanone (8)
Rf = 0.14 (EtOAc–hexanes, 1:1).
Apigenin (12)
To compound 5 (0.25 g) in toluene (10 mL) was added PTSA mono-
hydrate (0.15 g). The solution was heated overnight to 114 °C. After
the mixture had cooled to r.t., the toluene was removed by evapora-
tion. The residue was treated with H2O and extracted with EtOAc
(2 × 20 mL). The organic layers were washed with brine (10 mL)
and dried (MgSO4). Evaporation of the solvent and purification of
the residue by flash chromatography (hexanes–EtOAc, 2:1) afford-
ed the intermediate cyclized compound (0.16 g).
1H NMR (300 MHz, CDCl3): d = 6.35 (d, J = 2.1 Hz, 1 H), 6.67 (s,
1 H), 6.88 (d, J = 2.1 Hz, 1 H), 7.18 (m, 2 H), 7.51–7.61 (m, 5 H),
7.68–7.74 (m, 2 H), 7.81–7.92 (m, 5 H), 12.63 (s, 1 H).
1H NMR (300 MHz, CDCl3): d = 3.88 (s, 3 H), 3.91 (s, 3 H), 6.50
(d, J = 2.4 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 8.4 Hz,
1 H), 7.11–7.17 (m, 2 H), 7.40–7.42 (m, 4 H), 7.56–7.64 (m, 3 H),
7.69–7.73 (m, 1 H), 7.88–7.91 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 56.27, 56.32, 109.4, 109.9, 110.7,
111.7, 115.8, 125.7, 128.4, 128.6, 129.3, 129.7, 130.7, 134.6, 134.8,
135.0, 135.2, 147.8, 148.9, 152.7, 154.1, 161.4, 194.5.
MS: m/z = 570, 429, 287, 259, 164, 137.
HRMS: m/z calcd for C27H22O10S2: 570.0654; found: 570.0663.
To the above cyclized compound (50 mg, 0.090 mmol) and anhyd
K2CO3 (0.50 g) was added MeOH (20 mL). The mixture was heated
to 65 °C for 5 h. After the mixture had cooled to r.t., concd HCl was
added to neutralize the solution. The KCl salts were removed by fil-
tration. The filtrate was evaporated under vacuum. The residue was
recrystallized from MeOH (5 mL) and H2O (2 mL) to afford apige-
nin (12; 16 mg, 66%); Rf = 0.20 (EtOAc–hexanes, 1:1).
1H NMR (300 MHz, acetone-d6): d = 6.25 (d, J = 2.1 Hz, 1 H), 6.54
(d, J = 2.1 Hz, 1 H), 6.64 (s, 1 H), 7.02 (m, 2 H), 7.96 (m, 2 H),
13.03 (s, 1 H).
(2,4-Dimethoxy-6-hydroxyphenyl)(3-methoxy-4-benzyloxyphe-
nyl)methanone (9)
1H NMR (400 MHz, CDCl3): d = 11.75 (s, 1 H), 7.46–7.30 (m, 5 H),
7.23 (d, J = 1.6 Hz, 1 H), 7.15 (dd, J = 8.4, 1.6 Hz, 1 H), 6.87 (d,
J = 8.4 Hz, 1 H), 6.18 (d, J = 2.4 Hz, 1 H), 5.96 (d, J = 2.4 Hz, 1 H),
5.23 (s, 2 H), 3.91 (s, 3 H), 3.85 (s, 3 H), 3.50 (s, 3 H).
2,4-Dimethoxy-6-hydroxybenzophenone (10)
1H NMR (300 MHz, CDCl3): d = 3.46 (s, 3 H), 3.86 (s, 3 H), 5.93
(d, J = 2.4 Hz, 1 H), 6.17 (d, J = 2.4 Hz, 1 H), 7.34–7.43 (m, 2 H),
7.44–7.49 (m, 1 H), 7.50–7.57 (m, 2 H), 12.27 (s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 94.1, 99.0, 103.4, 104.7, 116.2,
122.6, 128.6, 158.1, 161.2, 162.7, 164.2, 164.4, 182.4.
Chrysin (11)
4,6-Dimethoxyaurone (13)
To compound 4 (0.30 g, 0.54 mmol) in toluene (20 mL) was added
PTSA monohydrate (0.30 g, 1.6 mmol). The solution was heated
overnight to 114 °C. After the mixture was cooled to r.t., toluene
was removed by evaporation under vacuum. The residue was treat-
ed with H2O and extracted with EtOAc (2 × 20 mL). The combined
organic layers were washed with brine (10 mL) and dried (MgSO4).
Evaporation of the solvent and purification of the residue by flash
chromatography (hexanes–EtOAc, 4:1) afforded the intermediate
cyclized compound with one benzenesulfonyloxy-protected group
(0.20 g, 90%); Rf = 0.42 (EtOAc–hexanes, 1:2).
To compound 6 (10 mg) and K2CO3 (10 mg) in a sealed tube was
added acetone (2 mL) and the mixture heated to 56 °C for 6 h. After
the solution had cooled to r.t., it was neutralized with 0.5 M aq
AcOH, diluted with H2O (20 mL) and extracted with EtOAc (2 × 5
mL). The combined organic layers were washed with brine (10 mL)
and dried (MgSO4). Evaporation of solvent and purification by flash
chromatography twice (hexanes–EtOAc, 2:1) afforded aurone 13
(9.5 mg, 95%) as a yellow solid; mp 148–151 °C (Lit.10b mp 152–
153 °C).
1H NMR (300 MHz, CDCl3): d = 3.93 (s, 1 H), 3.97 (s, 1 H), 6.15
(d, J = 1.8 Hz, 1 H), 6.41 (d, J = 1.8 Hz, 1 H), 6.79 (s, 1 H), 7.44 (m,
3 H), 7.88 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 6.34 (d, J = 2.1 Hz, 1 H), 6.74 (d,
J = 1.5 Hz, 1 H), 6.90 (d, J = 2.1 Hz, 1 H), 7.53–7.61 (m, 5 H),
7.69–7.73 (m, 1 H), 7.86–7.93 (m, 4 H).
3¢,4,4¢,6-Tetramethoxyaurone (14)
13C NMR (75 MHz, CDCl3): d = 101.9, 105.9, 106.4, 109.8, 126.7,
128.6, 129.5, 129.7, 130.8, 132.6, 135.0, 135.3, 154.4, 156.8, 162.2,
165.2, 183.0.
To a solution of 13 (25 mg, 0.073 mmol) in acetone (5 mL), taken
in a sealable tube, was added K2CO3 (31 mg, 0.22 mmol) at r.t. The
tube was sealed and the mixture heated for 6 h at 56 °C. The mixture
was cooled to r.t., passed through a pad of Celite, and then evapo-
rated in vacuo. The residue was purified by flash column chroma-
tography on silica gel (hexanes–EtOAc, 1:4) to afford aurone 14 (20
mg, 80%).
MS: m/z = 394, 393, 331,329, 301, 288, 151, 141, 123, 122, 121,
101, 77, 76, 75.
HRMS: m/z calcd for C21H14O6S: 394.0511; found: 394.0516.
To the above cyclized compound (60 mg, 0.15 mmol) and anhyd
K2CO3 (0.50 g) was added MeOH (20 mL). The mixture was heated
to 65 °C for 2 h. After the mixture had cooled to r.t., concd HCl was
added to neutralize the solution. The KCl salts were removed by fil-
tration. The filtrate was evaporated under vacuum. The residue was
dissolved in EtOAc (20 mL), washed with aq sat. NaHCO3 (20 mL),
brine (10 mL), and dried (MgSO4). Evaporation of the solvent and
purification by flash chromatography (hexanes–EtOAc, 4:1) af-
forded chrysin (11) (38 mg, ~100%); Rf = 0.25 (EtOAc–hexanes,
1:2).
1H NMR (300 MHz, acetone-d6): d = 6.28 (d, J = 2.1 Hz, 1 H), 6.58
(d, J = 2.1 Hz, 1 H), 6.80 (s, 1 H), 7.61 (m, 3 H), 8.07 (m, 2 H), 12.9
(s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 94.2, 99.2, 104.9, 105.5, 126.6,
129.3, 131.6, 132.1, 158.2, 162.7, 164.0, 164.4, 182.5.
1H NMR (400 MHz, CDCl3): d = 7.46–7.44 (m, 2 H), 6.93 (d,
J = 8.4 Hz, 1 Hz), 6.75 (s, 1 H), 6.36 (d, J = 1.6 Hz, 1 H), 6.14 (d,
J = 1.6 Hz, 1 H), 3.97 (s, 3 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 3.92 (s,
3 H).
LRMS (EI): m/z = 342 (M+, 100%), 311, 180.
HRMS (EI): m/z calcd for C19H18O6: 342.1103; found: 342.1108.
(2,4-Dimethoxy-6-hydroxyphenyl)-3¢-methoxy-4¢-hydroxyphe-
nylmethanone (15)
To a solution of benzophenone 9 (50 mg, 0.13 mmol) in a mixture
of MeOH–EtOAc (10:7, 17 mL) was added 10% Pd/C (30 mg). Af-
ter 18 h at r.t. under H2 atmosphere (H2 balloon), the mixture was
passed through a pad of Celite and then evaporated in vacuo. The
residue was purified by preparative TLC on silica gel (hexanes–
EtOAc, 2:1) to afford the natural product 1513 (28 mg, 73%).
1H NMR (400 MHz, CDCl3): d = 11.64 (s, 1 H), 7.25 (d, J = 2.0 Hz,
1 H), 7.16 (dd, J = 8.4, 2.0 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.18
Synthesis 2008, No. 15, 2427–2431 © Thieme Stuttgart · New York

PAPER
Reactions of Carbanions with 1,3-Benzodioxin-4-ones
(3) Marriott, J. H.; Barber, A. M. M.; Hardcastle, I. R.;
2431
(d, J = 2.4 Hz, 1 H), 6.04 (s, 1 H), 5.97 (d, J = 2.0 Hz, 1 H), 3.93 (s,
3 H), 3.86 (s, 3 H), 3.54 (s, 3 H).
Rowlands, M. G.; Grimshaw, R. M.; Neidle, S.; Jarman, M.
J. Chem. Soc., Perkin Trans. 1 2000, 4265.
13C NMR (100 MHz, CDCl3): d = 197.4, 166.0, 165.1, 161.6, 149.2,
146.1, 133.5, 124.3, 113.4, 111.0, 106.0, 93.9, 91.6, 56.3, 55.8,
55.4.
(4) Kamisuki, S.; Takahashi, S.; Mizushina, Y.; Hanashima, S.;
Kuramochi, K.; Kobayashi, S.; Sakaguchi, K.; Nakatab, T.;
Sugawara, F. Tetrahedron 2004, 60, 5695.
(5) Horne, S.; Rodrigo, R. J. Org. Chem. 1990, 55, 4520.
(6) The authentic sample was obtained from Aldrich Chemical
Company.
LRMS (EI): m/z = 304 (M+), 303 (100%), 287, 181.
HRMS (EI): m/z calcd for C16H16O6: 304.0947; found: 304.0952.
(7) Kartnig, T.; Goebel, I.; Heydel, B. Planta Med. 1996, 62, 51.
(8) Viola, H.; Wasowski, C.; Levi de Stein, M.; Wolfman, C.;
Silveira, R.; Dajas, F.; Medina, J. H.; Paladini, A. C. Planta
Med. 1995, 61, 213.
(9) Garcia, H.; Iborra, S.; Primo, J.; Miranda, M. A. J. Org.
Chem. 1986, 51, 4432.
(10) (a) Beney, C.; Mariotte, A. M.; Boumendjel, A.
Heterocycles 2001, 55, 967. (b) Geissman, T. A.;
Fukushima, D. K. J. Am. Chem. Soc. 1948, 70, 1686.
(11) Morimoto, M.; Fukumoto, H.; Nozoe, T.; Hagiwara, A.;
Komai, K. J. Agric. Food Chem. 2007, 55, 700.
(12) (a) Kosasi, S.; van der Sluis, W. G.; Labadie, R. P.
Phytochemistry 1989, 28, 2439. (b)Bohr, G.; Gerhauser, C.;
Knauft, J.; Zapp, J.; Becker, H. J. Nat. Prod. 2005, 68, 1545.
(13) Minami, H.; Kinoshita, M.; Fukuyama, Y.; Kodama, M.;
Yoshizawa, T.; Sugiura, M.; Nakagawa, K.; Tago, H.
Phytochemistry 1994, 36, 501.
Acknowledgment
We thank the National Institutes of Health (grant P01 ES12020) and
the Office of Dietary Supplements for partial financial support
through the Center for Research on Botanical Dietary Supplements
at Iowa State University.
References
(1) Oestreich, M.; Sempere-Culler, F.; Machotta, A. B. Angew.
Chem. Int. Ed. 2005, 44, 149.
(2) Mori, S.; Takechi, S.; Kida, S.; Mizui, T.; Ichihashi, T.
Shionogi and Co., Ltd., Japan, PCT Int. Appl. WO 9308155,
1993; Chem. Abstr. 1993, 119, 249697.
Synthesis 2008, No. 15, 2427–2431 © Thieme Stuttgart · New York