Preparative monohydroxyflavanone syntheses and a protocol for gas chromatography-mass spectrometry analysis of monohydroxyflavanones

Article abstract of DOI:10.1248/cpb.53.547

We describe a facile efficient, and preparative approach for monohydroxyflavanone syntheses. Using this protocol, a hydroxyl is regio-selectively introduced at one carbon of a flavanone A- or B-ring per synthesis. The seven possible isomers were each synthesized from the corresponding monomethoxymethoxylated 2′-hydroxychalcones in acidic solution. These monohydroxyflavanones were characterized using a gas chromatography-mass spectrometry (GC-MS) system that incorporated a DB-5 capillary column. Ours is the first report of a preparative synthetic method during which a single hydroxyl can be selectively added to a flavanone A- or B-ring at any position. We are also the first to develop a procedure that separates the seven isomers by GC and characterizes the mass spectra of the isomers. Both the synthetic method and the GC-MS conditions may become important tools during future flavanone metabolism and oxidation studies.

Full text of DOI:10.1248/cpb.53.547

May 2005
Chem. Pharm. Bull. 53(5) 547—554 (2005)
547
Preparative Monohydroxyflavanone Syntheses and a Protocol for Gas
Chromatography-Mass Spectrometry Analysis of Monohydroxyflavanones
a
Hitoshi KAGAWA,*,a Asako SHIGEMATSU,a Shigeru OHTA,b and Yoshihiro HARIGAYA
a Department of Organic Synthesis, School of Pharmaceutical Sciences, Kitasato University; 5–9–1 Shirokane, Minato-ku,
Tokyo 108–8641, Japan: and b Graduate School of Biomedical Sciences, Hiroshima University; 1–2–3 Kasumi, Minami-ku,
Hiroshima 734–8551, Japan. Received January 24, 2005; accepted February 28, 2005; published online March 2, 2005
We describe a facile efficient, and preparative approach for monohydroxyflavanone syntheses. Using this
protocol, a hydroxyl is regio-selectively introduced at one carbon of a flavanone A- or B-ring per synthesis. The
seven possible isomers were each synthesized from the corresponding monomethoxymethoxylated 2ꢀ-hydroxy-
chalcones in acidic solution. These monohydroxyflavanones were characterized using a gas chromatography-
mass spectrometry (GC-MS) system that incorporated a DB-5 capillary column. Ours is the first report of a
preparative synthetic method during which a single hydroxyl can be selectively added to a flavanone A- or B-ring
at any position. We are also the first to develop a procedure that separates the seven isomers by GC and charac-
terizes the mass spectra of the isomers. Both the synthetic method and the GC-MS conditions may become im-
portant tools during future flavanone metabolism and oxidation studies.
Key words monohydroxyflavanone; GC-MS; chalcone; flavonoid
Flavonoids are phenolic compounds found in most plants. ol derivatives were produced when several different fla-
Since flavonoids are naturally present in fruits, vegetables, vanones were substrates.19) Therefore, although all flavonoids
and tea, they are an integral part of the human diet.1) Ingested have a common three-ring skeleton, it appears that ring sub-
flavonoids are absorbed by the gastrointestinal tract and have stituents determine the metabolic fate of a specific substrate.
been found in blood plasma.2) Flavonoids possess various bi-
If demethylated and hydroxylated flavonoid P450 meta-
ological and pharmacological properties, such as antioxidant bolic products, amongst others, are to be unequivocally char-
activity,3) anti-HIV-1 activity,4) and anti-inflammatory activ- acterized, their physical properties must be compared with
ity.5) They seem to protect against cancer onset,6) vascular de- known standards. Previously, we reported a synthetic proce-
mentia,7) and coronary heart disease-related deaths.8) dure for (ꢁ)-2,3-trans-flavanonols, which are hydroxylated at
Flavonoids also modulate the activities of enzymes that me- the C-3 position.20,21) Consequently, only those compounds
tabolize drugs.9) Flavonoids form the largest class of phytoe- could be unquestionably identified as P450 metabolic prod-
strogens known. The binding affinity of a flavonoid for the ucts during our previous study.16) In order to identify other
estrogen receptor primarily depends on the positions of A- metabolic monohydroxyflavanones, we have now developed
and C-ring hydroxyl groups.10) Recently, two interesting procedures to synthetically produce these compounds and to
pharmacological properties of flavonoids have been reported. identify them by GC-MS analysis.
1) The polymethoxyflavone, tangeretin, protects against the
development of experimentally-induced Parkinson’s disease Results and Discussion
in rats.11) 2) Other polymethoxyflavones inhibit the cellular
Usually, the chemical synthesis of a flavanone involves cy-
excretion of certain drugs—a process mediated by P-glyco- clization of the corresponding chalcone in acidic solution. In
protein.12,13) Cytochrome P450s can remove a flavonoid C-4ꢀ turn, the chalcone is usually synthesized from derivatives of
methyl and can add a hydroxyl at the C-3ꢀ position.14,15) To acetophenone and benzaldehyde by an aldol reaction. Mono-
understand the diverse pharmacological effects of dietary hydroxyflavanones have also usually been prepared by this
flavonoids, their metabolic pathways must be known.
route.22) However, because product yields are usually low,
A previous study of ours16) showed that both rat and this method is not practical. While 5-hydroxyflavanone can
human cytochrome P450s convert flavanones to the corre- be directly synthesized from acetophenone and benzaldehyde
sponding 2,3-trans-flavanonols and flavones; whereas, only in the presence of silica gel, boric acid, and piperidine,23)
the human enzyme can convert the flavanone to isoflavone. other monohydroxyflavanones cannot be synthesized using
We also recently reported a procedure for the specific deuter- analogous procedures. As mentioned above, we have pre-
ation of flavanones.17) With these deuterated flavanones as pared 2,3-trans-flavanonols (3-hydroxyflavanones), in high
substrates, we determined that, most likely, the initial step in yields, from chalcone epoxides.20,21)
flavanone P450-catalyzed metabolism is abstraction of a hy-
drogen radical from the C-2 or -3 position of the flavanone hydroxyflavanone syntheses and report that work here. Nine
skeleton. different monohydroxyflavanone isomers potentially exist.
We have now applied this method to regio-selective mono-
After rats received flavanone via a stomach tube, the most However, the monohydroxyflavanone that has a hydroxyl at
common urinary metabolites found were those with the C-4 position C-2 of ring C is unstable. Dehydration typically oc-
ketone reduced and those with hydroxyls added at positions curs and the corresponding flavone is produced. As noted, we
C-3 and C-6.18) Another P450 metabolic study found that have already reported a method for hydroxylation at position
aromatic hydroxylation products, flavones, unusual quinol- C-3 of ring C. Now, we report the synthesis of the other
type oxidation products, chromone derivatives, and flavan-4- seven monohydroxyflavanones (compounds 4a—g; Chart 1)
∗ To whom correspondence should be addressed. e-mail: kagawah@pharm.kitasato-u.ac.jp
© 2005 Pharmaceutical Society of Japan

548
Vol. 53, No. 5
Chart 1. Synthetic Route of Monohydroxyflavanone 4a—g
Table 1. Synthesis of 2ꢀ-Hydroxy-monomethoxymethoxyacetophenone
1a—d
Substrate
OH
Temp.
Product
OMOM
Yield (%)
Chart 2. Synthesis of 2ꢀ,3ꢀ-Dihydroxyacetophenone 7a
7a
7b
7c
7d
3ꢀ
4ꢀ
5ꢀ
6ꢀ
r.t.
r.t.
reflux
r.t.
1a
1b
1c
1d
3ꢀ
4ꢀ
5ꢀ
6ꢀ
72.4a)
96.8
72.8
92.8
and also report conditions for GC-MS that separate the com-
pounds and characterize their fragmentation patterns.
To regio-selectively synthesize these monohydroxyfla-
vanones (Chart 1), we first protected the (non-C-2ꢀ) hydroxyl
of an acetophenone derivative (7a—d) or the hydroxyl of a
benzaldehyde derivative (8a—c) by reaction with methoxy-
methyl chloride (MOMCl) in the presence of N-ethyldiiso-
propylamine (DIPEA). During chalcone synthesis (in the
presence of base) the hydroxyl remains protected; whereas,
during the flavanone synthesis that follows, the methoxy-
methyl group is readily removed as a consequence of the
acidic condition. When the aldol reaction (using acetophe-
none and benzaldehyde derivatives as reagents and producing
a chalcone) is performed in basic solution—a condition for
which the reaction proceeds smoothly—the acetophenone C-
2ꢀ hydroxyl need not be protected.
To produce monohydroxylated A-ring flavanones, pro-
tected monohydroxylated 2ꢀ-hydroxyacetophenones 1a—d,
the products of reaction of compounds 7a—d with MOMCl,
were the reagents. To produce monohydroxylated B-ring fla-
vanones, protected monohydroxylated benzaldehydes 2a—c
were the reagents.
a) The yield of 3ꢀ-hydroxy-2ꢀ-methoxymethoxyacetophenone 1aꢀ was 7.0% and
2ꢀ,3ꢀ-dimethoxymethoxyacetophenone 1aꢁ was 16.0%.
Table 2. Synthesis of Monomethoxymethoxybenzaldehyde 2a—c
Substrate
OH
Product
OMOM
Yield (%)
8a
8b
8c
2
3
4
2a
2b
2c
2
3
4
96.9
81.8
99.2
(Table 1). Protection of 7a produced 2ꢀ-hydroxy-3ꢀ-methoxy-
methoxyacetophenone (1a, 72.4% yield), 3ꢀ-hydroxy-2ꢀ-
methoxymethoxyacetophenone (1aꢀ, 7.0% yield), and 2ꢀ,3ꢀ-
dimethoxymethoxyacetophenone (1aꢁ, 16.0% yield). Com-
pound 7c, 2ꢀ,5ꢀ-dihydroxyacetophenone, is insoluble in
CH2Cl2 at room temperature; therefore, to solubilize 7c, the
reaction mixture was refluxed.
For synthesis of B-ring monohydroxyflavanones, MOM-
protected monohydroxybenzaldehydes 2a—c were synthe-
sized using monohydroxybenzaldehydes 8a—c as the start-
ing materials. Compounds 2a—c were obtained in good
yields (Table 2).
Baker et al.24) reported the synthesis of 2ꢀ,3ꢀ-dihydroxy-
acetophenone, 7a, (Chart 2). Applying this Grignard reac-
tion, we found that 2,3-dimethoxybenzonitrile, 5, was con-
verted to 2ꢀ-hydroxy-3ꢀ-methoxyacetophenone, 6a, (57.2%
yield) and 2ꢀ,3ꢀ-dimethoxyacetophenone, 6b, (14.4% yield).
Perhaps Grignard reagent reacted with 6b and deprotected
the hydroxyl ortho to the carbonyl to produce 6a.25) De-
methylation of 6a by BBr3 produced 7a (81.5% yield).
For synthesis of A-ring monohydroxyflavanones, 2ꢀ-hy-
droxyacetophenones 7a—d that were also hydroxylated at
positions C-3ꢀ, -4ꢀ, -5ꢀ or -6ꢀ, were protected using MOMCl
The 2ꢀ-hydroxy-monomethoxymethoxychalcones 3a—g
were synthesized from the protected acetophenones 1a—d

May 2005
549
and benzaldehyde, 2, or from acetophenone, 1, and the pro- tained in good chemical yield. During cyclization and depro-
tected benzaldehydes 2a—c by base-catalyzed aldol reac- tection, the 2ꢀ-hydroxy-monohydroxychalcones 3aꢀ—dꢀ
tions (Tables 3, 4). During the synthesis of 2ꢀ-hydroxy-5ꢀ- were also produced. It was hard to isolate the dihydroxychal-
methoxymethoxychalcone, 3c, 6-methoxymethoxyflavanone, cone 3aꢀ because it absorbed tightly to silica gel. The dihy-
4cꢀ, was formed in 26.4% yield as a side product. We assume droxychalcone 3dꢀ was also difficult to isolate because it
that 4cꢀ was produced from the p-quinone of 3c. Compound readily converted to 4d in the presence of silica gel. With the
4cꢀ was converted to 4c in the presence of 12% HCl–MeOH exception of 3aꢀ, the other dihydroxychalcones (3bꢀ—dꢀ)
(95.8% yield).
could be converted to the monohydroxyflavanones 4b—d
The 2ꢀ-hydroxy-monomethoxymethoxychalcones 3a—g using acid (data not shown).
were cyclized and deprotected in acidic solution to produce
To deprotect the B-ring hydroxyls and form the monohy-
the monohydroxyflavanones 4a—g. For flavanones monohy- droxyflavanones 4e—g, monomethoxymethoxychalcones
droxylated at the A-ring (4a—d), the corresponding chal- 3e—g were also reacted with HCl–MeOH (Table 6). Both
cones 3a—d were treated with 17.8 or 25.8% HCl–MeOH at monohydroxyflavanones 4e—g and dihydroxychalcones
100 °C (Table 5). Monohydroxyflavanones 4a—d were ob- 3eꢀ—gꢀ were produced when 3e—g were reacted with
HCl–MeOH. After isolation, the dihydroxychalcones 3eꢀ—gꢀ
were also converted to the monohydroxyflavanones 4e—g by
Table 3. Synthesis of 2ꢀ-Hydroxy-monomethoxymethoxychalcone 3a—d
Table 4. Synthesis of 2ꢀ-Hydroxy-monomethoxymethoxychalcone 3e—g
Substrate
OMOM
Product
OMOM
Yield (%)
1a
1b
1c
1d
3ꢀ
4ꢀ
5ꢀ
6ꢀ
3a
3b
3c
3d
3ꢀ
4ꢀ
5ꢀ
6ꢀ
91.0
Substrate
OMOM
Product
OMOM
Yield (%)
69.2 (93.2)a)
60.7b)
2a
2b
2c
2
3
4
3e
3f
3g
2
3
4
81.2
73.6
81.3
90.0
a) Based on recovered. b) The yield of 6-methoxymethoxyflavanone 4cꢀ was
26.4%.
Table 5. Synthesis of Monohydroxyflavanone 4a—d
Substrate
OMOM
HCl–MeOH (%)
Flavanone
OH
Yield (%)
Chalcone
OH
Yield (%)
3a
3b
3c
3d
3ꢀ
5ꢀ
5ꢀ
6ꢀ
25.8
25.8
17.8
17.8
4a
4b
4c
4d
8
7
6
5
74.1
71.4
91.1
82.2
3aꢀ
3bꢀ
3cꢀ
3dꢀ
3ꢀ
4ꢀ
5ꢀ
6ꢀ
—
27.9
8.8
—
Table 6. Synthesis of Monohydroxyflavanone 4e—g
Substrate
OMOM
Flavanone
OH
Yield (%)
Chalcone
OH
Yield (%)
3e
3f
3g
2
3
4
4e
4f
4g
2ꢀ
3ꢀ
4ꢀ
66.0
81.8
63.2
3eꢀ
3fꢀ
3gꢀ
2
3
4
24.8
14.0
34.3

550
Vol. 53, No. 5
Fig. 1. Total Ion Chromatogram (TIC) and Mass Chromatogram of Monohydroxyflavanone 4a—g
AX505 HA mass spectrometer (for high-resolution mass spectrometry). For
thin-layer chromatography, samples were chromatographed through silica
gel 60 PF254 (Merck) and were detected in the presence of ultraviolet (u.v.)
light at 254 and 365 nm. Column chromatography was performed using
Wakogel C-200 silica gel. Elemental analyses were performed using a
Yanaco CHN Coder MT-5. A 25.8% HCl–MeOH solution was prepared by
bubbling HCl gas into MeOH. Other HCl–MeOH solutions were prepared
by diluting this 25.8% HCl solution with MeOH.
Analysis by GC-MS GC-MS analysis was performed using a model
JMS-AX505 HA mass spectrometer from Jeol (Tokyo, Japan), a gas chro-
matograph (5890 series II; Hewllet Packard, Palo Alto, CA, U.S.A.), a 30-m
DB-5 capillary column (i.d., 0.25 mm; J & W Scientific, Palo Alto, CA,
U.S.A.). The injection temperature, interface temperature, ionizing voltage,
ionizing current, accelerating voltage, temperature of the ion source and the
reaction with acid (data not shown.)
Although in this report, we have only shown that monohy-
droxyflavanones can be readily synthesized, we expect that
similar procedures can be used to synthesize flavanones with
multiple hydroxyl groups added to rings A and B.
Using GC in conjunction with a DB-5 capillary column,
the seven monohydroxyflavanones, 4a—g, were separated
(Fig. 1A). Monohydroxyflavanones 4a—d, which are hy-
droxylated at the A-ring, have a characteristic fragmentation
ion with a m/z of 136 (Fig. 1B). For the B-ring monohydroxy-
flavanones, 4e—g, the characteristic fragmentation ion m/z is
121 (Fig. 1C). We propose the structure of these fragmenta- flow rate of helium were set at 250 °C, 280 °C, 70 eV, 300 mA, 3 kV, 250 °C
tion ions according to Van de Sande26) and Nikolic.19) Mono-
hydroxyflavanone 4a—g have also characteristic fragmenta-
tion ions with a m/z of 163 or 147. These fragmentation ions
and 30 ml/min respectively. The initial temperature of the column was
100 °C. After 1 min, it was raised at 15 °C/min to 220 °C. After 4 min at
220 °C, it was raised at 5 °C/min to 250 °C and then the temperature was
maintained at 250 °C. One mM acetone solution (0.5 ml) of all monohydrox-
yflavanones mixture was subjected to analysis by GC-MS.
2ꢀ-Hydroxy-3ꢀ-methoxyacetophenone (6a) and 2ꢀ,3ꢀ-Dimethoxyace-
tophenone (6b) 2,3-Dimethoxybenzonitrile (5, 5.1041 g, 31.3 mmol) dis-
solved in anhydrous ether (30 ml) was added to a solution of methylmagne-
sium iodide, which had been prepared from magnesium (0.754 g), methyl io-
dide (4.0 ml, 64.3 mmol), and ether (20 ml). After 16 h reaction time, the
mixture was refluxed for 2 h, decomposed by addition of dilute acetic acid,
and extracted with CH2Cl2 (250 ml). The organic layer was isolated, washed
with 70 ml saturated Na2CO3, dried over Na2SO4, and evaporated. The
residue was a pale yellowish crystalline substance that was chromatographed
over a column of silica gel in n-hexane and acetone (10 : 1) to purify 6a
(2.9747 g, yield 57.2%) and 6b (0.8129 g, yield 14.4%).
are due to the loss of phenyl radical from a flavanone skele-
ton. Therefore, observation of these fragmentation ions dur-
ing characterization of flavanone metabolites or oxidation
products will identify which ring is monohydroxylated. Re-
tention times, in conjunction with mass fragmentation pat-
terns, can be used to identify the flavanone hydroxylation
site.
In conclusion, ours is the first report of a facile and effi-
cient procedure for the preparative synthesis of flavanones
monohydroxylated at any one specific site in the A or B ring
and is also the first report of a GC-MS protocol that identifies
all seven isomers.
2ꢀ-Hydroxy-3ꢀ-methoxyacetophenone (6a): Pale yellowish needles,
Rfꢂ0.24 (n-hexane : acetoneꢂ5 : 1); mp: 54 °C (EtOH) (lit.27) 50—53.1 °C);
IR (CHCl3) cmꢃ1: 1638 (CꢂO); 1H-NMR (300 MHz, CDCl3) d: 12.558 (1H,
d, Jꢂ0.5 Hz, 2-OH), 7.336 (1H, dd, Jꢂ1.5, 8.0 Hz, 6-H), 7.054 (1H, ddd,
Experimental
General Melting points were determined using a Yanagimoto micro Jꢂ0.5, 8.0, 1.5 Hz, 4-H), 6.840 (1H, t, Jꢂ8.0 Hz, 5-H), 3.898 (3H, s, 3-
melting apparatus and are reported as uncorrected values. IR spectra were OCH3), 2.632 (3H, s, COCH3); HR-EI-MS m/z: 166.0628 (Calcd for
acquired using a Hitachi 260-30 spectrometer.
C9H10O3: 166.0630); Anal. Calcd for C9H10O3: C, 65.05, H, 6.07; Found: C,
1H-NMR spectra were acquired using a Varian VXR-300 (300 MHz) or a 64.95, H, 6.12.
Varian XL-400 (400 MHz) spectrometer. All NMR samples were dissolved
2ꢀ,3ꢀ-Dimethoxyacetophenone (6b): Pale yellowish oil, Rfꢂ0.31 (n-
in CDCl3. Mass spectra were obtained using a JEOL-JMX-DX 505 H mass hexane : acetoneꢂ5 : 1); IR (CHCl3) cmꢃ1
:
1678 (CꢂO); 1H-NMR
spectrometer (for low-resolution mass spectrometry) and a JEOL-JMS- (300 MHz, CDCl3) d: 7.219 (1H, dd, Jꢂ2.2, 7.2 Hz, 6-H), 7.085 (1H, dd,

May 2005
551
Jꢂ8.0, 7.2 Hz, 5-H), 7.043 (1H, dd, Jꢂ8.0, 2.2 Hz, 7-H), 3.905 (3H, s, 2-
OCH3), 3.892 (3H, s, 3-OCH3), 2.627 (3H, s, COCH3); HR-EI-MS m/z:
180.0787 (Calcd for C10H12O3: 180.0786); Anal. Calcd for C10H12O3: C,
66.65, H, 6.71; Found: C, 66.62, H, 6.85.
6.615 (1H, dd, Jꢂ1.0, 8.5 Hz, 3ꢀ-H), 6.595 (1H, dd, Jꢂ1.0, 8.0 Hz, 5ꢀ-H),
5.283 (2H, s, 6ꢀ-OCH2OCH3), 3.525 (3H, s, 6ꢀ-OCH2OCH3), 2.718 (3H, s,
COCH3); HR-EI-MS m/z: 196.0725 (Calcd for C10H12O4: 196.0736), Anal.
Calcd for C10H12O4: C, 61.22, H, 6.16; Found: C, 61.02, H, 6.24.
2ꢀ,3ꢀ-Dihydroxyacetophenone (7a) Under argon, 1 ml of 1.0 M BBr3,
2-Methoxymethoxybenzaldehyde (2a) To a solution of 2-hydroxybenz-
dissolved in (CHCl2)2, was added to 2 ml 2ꢀ-hydroxy-3ꢀ-methoxyacetophe- aldehyde (8a, 4.0084 g, 32.8 mmol) and DIPEA (17.1 ml, 98.2 mmol) in
none (6a, 99.8 mg, 0.6 mmol) dissolved in CH2Cl2. The mixture was stirred
at room temperature for 2.0 h. Water was added and the mixture was ex-
CH2Cl2 (45 ml), MOMCl (4.0678 g, 50.5 mmol) was added. The mixture
was stirred at room temperature for 2 h. Water was added and the mixture
tracted with ethyl acetate. The organic layer was dried over Na2SO4, and was extracted with CH2Cl2. The organic layer was dried over Na2SO4, and
evaporated. The residue was purified using preparative TLC (silica gel, n- evaporated. The residue was chromatographed over a column of silica gel in
hexane : acetoneꢂ10 : 1) to give 7a (74.5 mg, yield 81.5%) as a pale yellow- benzene to purify 2a (5.2848 g, 96.9%) as a pale brownish oil, Rfꢂ0.29
1
ish prisms. Rfꢂ0.21 (n-hexane : acetoneꢂ5 : 1); mp: 100—102 °C (benzene)
(benzene); IR (CHCl3) cmꢃ1: 1685 (CHO); H-NMR (400 MHz, CDCl3) d:
(lit.24) 97 °C); IR (CHCl3) cmꢃ1: 1640 (CꢂO); H-NMR (300 MHz, CDCl3) 10.058 (1H, d, Jꢂ1.0 Hz, CHO), 7.843 (1H, dd, Jꢂ2.0, 8.0 Hz, 6-H), 7.531
1
d: 12.461 (1H, d, Jꢂ0.5 Hz, 2-OH), 7.287 (1H, dd, Jꢂ1.5, 8.0 Hz, 6-H),
7.132 (1H, ddd, Jꢂ0.5, 1.5, 8.0 Hz, 4-H), 6.823 (1H, dd, Jꢂ8.0 Hz, 5-H),
(1H, ddd, Jꢂ2.0, 7.5, 8.5 Hz, 4-H), 7.218 (1H, dd, Jꢂ1.0, 8.5 Hz, 3-H),
7.082 (1H, ddd, Jꢂ1.0, 7.5, 8.0 Hz, 5-H), 5.305 (2H, s, 2-OCH2OCH3),
5.752 (1H, br, 3-OH), 2.632 (3H, s, COCH3); HR-EI-MS m/z: 152.0471 3.524 (3H, s, 2-OCH2OCH3); HR-EI-MS m/z: 166.0618 (Calcd for C9H10O3:
(Calcd for C8H8O3: 152.0473); Anal. Calcd for C8H8O3: C, 63.15, H, 5.30; 166.0630); Anal. Calcd for C9H10O3: C, 65.05, H, 6.07; Found: C, 64.75, H,
Found: C, 63.24, H, 5.31.
2ꢀ-Hydroxy-3ꢀ-methoxymethoxyacetophenone (1a), 3ꢀ-Hydroxy-2ꢀ-
6.00.
3-Methoxymethoxybenzaldehyde (2b) and 4-Methoxymethoxybenz-
methoxymethoxyacetophenone (1aꢀ), and 2ꢀ,3ꢀ-Dimethoxymethoxyace- aldehyde (2c) Compounds 2b and 2c were synthesized starting with the
tophenone (1aꢁ) To solution of 2ꢀ,3ꢀ-dihydroxyacetophenone (7a, corresponding monohydroxybenzaldehydes 8b and 8c using procedures sim-
a
0.9590 g, 6.3 mmol) and DIPEA (2.7 ml, 15.5 mmol) in CH2Cl2 (20 ml),
MOMCl (0.7618 g, 9.5 mmol) was added. The mixture was stirred at room
temperature for 1 h. Water was then added and the mixture was extracted
ilar to that described for preparation of 2a.
3-Methoxymethoxybenzaldehyde (2b): Colorless oil, Rfꢂ0.33 (benzene);
1
IR (CHCl3) cmꢃ1: 1698 (CHO); H-NMR (400 MHz, CDCl3) d: 9.975 (1H,
with ethyl acetate. The organic layer was dried over Na2SO4, and evaporated. s, CHO), 7.547 (1H, ddd, Jꢂ0.5, 1.0, 2.5 Hz, 2-H), 7.527 (1H, dt, Jꢂ1.0,
The residue was chromatographed over a column of silica gel in a 5 : 1 n- 7.5 Hz, 6-H), 7.453 (1H, ddd, Jꢂ0.5, 7.5, 8.0 Hz, 5-H), 7.298 (1H, ddd,
hexane : acetone mixture to separate 1a (0.8909 g, yield 72.4%), 1aꢀ Jꢂ1.0, 2.5, 8.0 Hz, 4-H), 5.230 (2H, s, 3-OCH2OCH3), 3.489 (3H, s, 3-
(0.0871 g, yield 7.0%), and 1aꢁ (0.2425 g, yield 16.0%).
OCH2OCH3); HR-EI-MS m/z: 166.0616 (Calcd for C9H10O3: 166.0630),
2ꢀ-Hydroxy-3ꢀ-methoxymethoxyacetophenone (1a): Pale yellowish oil, Anal. Calcd for C9H10O3: C, 65.05, H, 6.07; Found: C, 65.08, H, 6.18.
Rfꢂ0.28 (n-hexane : acetoneꢂ5 : 1); IR (CHCl3) cmꢃ1: 1643 (CꢂO); 1H-
NMR (300 MHz, CDCl3) d: 12.529 (1H, d, Jꢂ0.5 Hz, 2ꢀ-OH), 7.425 (1H,
dd, Jꢂ1.5, 8.0 Hz, 6ꢀ-H), 7.340 (1H, ddd, Jꢂ0.5, 1.5, 8.0 Hz, 4ꢀ-H), 6.828
4-Methoxymethoxybenzaldehyde (2c): Colorless oil, Rfꢂ0.22 (benzene);
1
IR (CHCl3) cmꢃ1: 1690 (CHO); H-NMR (300 MHz, CDCl3) d: 9.900 (1H,
s , CHO), 7.835 (2H, d, Jꢂ9.0 Hz, 2,6-Hs), 7.145 (2H, d, Jꢂ9.0 Hz, 3,5-Hs),
(1H, t, Jꢂ8.0 Hz, 5ꢀ-H), 5.245 (2H, s, 3ꢀ-OCH2OCH3), 3.527 (3H, s, 3ꢀ- 5.252 (2H, s, 4-OCH2OCH3), 3.490 (3H, s, 4-OCH2OCH3); HR-EI-MS m/z:
OCH2OCH3), 2.635 (3H, s, COCH3); HR-EI-MS m/z: 196.0744 (Calcd for 166.0629 (Calcd for C9H10O3: 166.0630), Anal. Calcd for C9H10O3: C,
C10H12O4: 196.0736); Anal. Calcd for C10H12O4: C, 61.22, H, 6.16; Found: 65.05, H, 6.07; Found: C, 64.95, H, 6.05.
C, 61.24, H, 6.21.
2ꢀ-Hydroxy-3ꢀ-methoxymethoxychalcone (3a) A mixture of 2ꢀ-hy-
3ꢀ-Hydroxy-2ꢀ-methoxymethoxyacetophenone (1aꢀ): Pale yellowish oil, droxy-3ꢀ-methoxymethoxyacetophenone (1a, 0.5761 g, 2.9 mmol), benzalde-
Rfꢂ0.10 (n-hexane : acetoneꢂ5 : 1); IR (CHCl3) cmꢃ1: 1681 (CꢂO); 1H-
hyde (2, 0.4676 g, 4.4 mmol), and KOH (0.8431 g, 15.0 mmol) in EtOH
NMR (300 MHz, CDCl3) d: 7.440 (1H, br, 3ꢀ-OH), 7.150—7.040 (3H, m, (10 ml) was stirred at room temperature for 22.5 h. Then the mixture was
4ꢀ,5ꢀ,6ꢀ-Hs), 5.075 (2H, s, 2ꢀ-OCH2OCH3), 3.625 (3H, s, 2ꢀ-OCH2OCH3),
2.558 (3H, s, COCH3); HR-EI-MS m/z: 196.0737 (Calcd for C10H12O4:
neutralized by addition of 10% AcOH in EtOH. This mixture was evapo-
rated and the residue was extracted with ethyl acetate. The organic layer was
196.0736); Anal. Calcd for C10H12O4: C, 61.22, H, 6.16; Found: C, 61.15, H, dried over Na2SO4, and evaporated. The residue was purified using prepara-
6.25. tive TLC (benzene : ethyl acetateꢂ20 : 1) to give 3a (0.7541 g, yield 91.0%)
2ꢀ,3ꢀ-Dimethoxymethoxyacetophenone (1aꢁ): Pale yellowish oil, Rfꢂ0.21 as an orange prisms. Rfꢂ0.34 (benzene : ethyl acetateꢂ20 : 1); mp: 76.5—
(n-hexane : acetoneꢂ5 : 1); IR (CHCl3) cmꢃ1 1685 (CꢂO); 1H-NMR 77 °C (EtOH); IR (CHCl3) cmꢃ1: 1638 (CꢂO), 1H-NMR (300 MHz, CDCl3)
:
(300 MHz, CDCl3) d: 7.273 (1H, dd, Jꢂ2.0, 8.0 Hz, 4ꢀ-H), 7.208 (1H, dd, d: 13.115 (1H, d, Jꢂ0.5 Hz, 2ꢀ-OH), 7.940 (1H, d, Jꢂ15.5 Hz, b-H),
Jꢂ2.0, 8.0 Hz, 6ꢀ-H), 7.077 (1H, t, Jꢂ8.0 Hz, 5ꢀ-H), 5.210 (2H, s, 3ꢀ- 7.720—7.640 (2H, m, 2,6-Hs), 7.650 (1H, d, Jꢂ15.5 Hz, a-H), 7.620 (1H,
OCH2OCH3), 5.148 (2H, s, 2ꢀ-OCH2OCH3), 3.510 (3H, s, 3ꢀ-OCH2OCH3), dd, Jꢂ1.0, 8.0 Hz, 6ꢀ-H), 7.480—7.410 (3H, m, 3,4,5-Hs), 7.380 (1H, ddd,
3.500 (3H, s, 2ꢀ-OCH2OCH3), 2.637 (3H, s, COCH3); HR-EI-MS m/z:
240.1005 (Calcd for C14H18O5: 240.0998); Anal. Calcd for C10H12O4: C,
59.99, H, 6.71; Found: C, 60.18, H, 6.67.
Jꢂ0.5, 1.0, 8.0 Hz, 4ꢀ-H), 6.853 (1H, dd, Jꢂ8.0 Hz, 5ꢀ-H), 5.280 (2H, s, 3ꢀ-
OCH2OCH3), 3.550 (3H, s, 3ꢀ-OCH2OCH3); HR-EI-MS m/z: 284.1052
(Calcd for C17H16O4: 284.1049); Anal. Calcd for C17H16O4: C, 71.82, H,
2ꢀ-Hydroxy-4ꢀ-methoxymethoxyacetophenone (1b), 2ꢀ-Hydroxy-5ꢀ- 5.67; Found: C, 71.94, H, 5.75.
methoxymethoxyacetophenone (1c), and 2ꢀ-Hydroxy-6ꢀ-methoxyme-
thoxyacetophenone (1d) Compounds 1b—d were synthesized starting
with the corresponding dihydroxyacetophenones 7b—d using procedures
similar to that described for the preparation of 1a.
2ꢀ-Hydroxy-4ꢀ-methoxymethoxychalcone (3b), 2ꢀ-Hydroxy-5ꢀ-me-
thoxymethoxychalcone (3c) and 2ꢀ-Hydroxy-6ꢀ-methoxymethoxychal-
cone (3d) Compounds (3b—d) were prepared from the corresponding
monomethoxymethoxylated derivatives of 2ꢀ-hydroxyacetophenone (1b—d)
2ꢀ-Hydroxy-4ꢀ-methoxymethoxyacetophenone (1b): Pale yellowish oil, using procedures similar to that described for preparation of 3a.
Rfꢂ0.20 (benzene); IR (CHCl3) cmꢃ1: 1632 (CꢂO); 1H-NMR (300 MHz,
CDCl3) d: 12.605 (1H, s, 2ꢀ-OH), 7.648 (1H, d, Jꢂ9.0 Hz, 6ꢀ-H), 6.593 (1H,
2ꢀ-Hydroxy-4ꢀ-methoxymethoxychalcone (3b): Yellow needles, Rfꢂ0.36
1
(benzene); mp: 85.5 °C (EtOH); IR (CHCl3) cmꢃ1: 1637 (CꢂO); H-NMR
d, Jꢂ2.5 Hz, 3ꢀ-H), 6.547 (1H, dd, Jꢂ2.5, 9.0 Hz, 5ꢀ-H), 5.205 (2H, s, 4ꢀ- (300 MHz, CDCl3) d: 13.262 (1H, s, 2ꢀ-OH), 7.905 (1H, d, Jꢂ15.5 Hz, b-
OCH2OCH3), 3.475 (3H, s, 4ꢀ-OCH2OCH3), 2.565 (3H, s, COCH3); HR-EI- H), 7.855 (1H, d, Jꢂ9.0 Hz, 6ꢀ-H), 7.685—7.090 (2H, m, 2,6-Hs), 7.585
MS m/z: 196.0743 (Calcd for C10H12O4: 196.0736), Anal. Calcd for (1H, d, Jꢂ15.5 Hz, a-H), 7.465—7.400 (3H, m, 3,4,5-Hs), 6.653 (1H, d,
C10H12O4: C, 61.22, H, 6.16; Found: C, 61.36, H, 6.25. Jꢂ2.5 Hz, 3ꢀ-H), 6.598 (1H, dd, Jꢂ2.5, 9.0 Hz, 5ꢀ-H), 5.231 (2H, s, 4ꢀ-
2ꢀ-Hydroxy-5ꢀ-methoxymethoxyacetophenone (1c): The reaction mixture OCH2OCH3), 3.495 (3H, s, 4ꢀ-OCH2OCH3); HR-EI-MS m/z: 284.1054
containing 7c was refluxed for 1 h. Pale yellowish oil, Rfꢂ0.23 (benzene); (Calcd for C17H16O4: 284.1049); Anal. Calcd for C17H16O4: C, 71.82, H,
IR (CHCl3) cmꢃ1: 1645 (CꢂO), 1H-NMR (300 MHz, CDCl3) d: 11.910 (1H, 5.67; Found: C, 71.62, H, 5.71.
s, 2ꢀ-OH), 7.390 (1H, d, Jꢂ3.0 Hz, 6ꢀ-H), 7.224 (1H, dd, Jꢂ3.0, 9.0 Hz, 4ꢀ-
H), 6.917 (1H, d, Jꢂ3.0 Hz, 3ꢀ-H), 5.125 (2H, s, 5ꢀ-OCH2OCH3), 3.497 (3H, (benzene); mp: 67.5 °C (EtOH); IR (CHCl3) cmꢃ1: 1640 (CꢂO); H-NMR
s, 5ꢀ-OCH2OCH3), 2.614 (3H, s, COCH3); HR-EI-MS m/z: 196.0745 (Calcd (300 MHz, CDCl3) d: 12.450 (1H, s, 2ꢀ-OH), 7.933 (1H, d, Jꢂ15.5 Hz, b-
for C10H12O4: 196.0736); Anal. Calcd for C10H12O4: C, 61.22, H, 6.16; H), 7.700—7.650 (2H, m, 2,6-Hs), 7.598 (1H, d, Jꢂ15.5 Hz, a-H), 7.578
Found: C, 61.36, H, 6.36. (1H, d, Jꢂ3.0 Hz, 6ꢀ-H), 7.480—7.430 (3H, m, 3,4,5-Hs), 7.280 (1H, dd,
2ꢀ-Hydroxy-6ꢀ-methoxymethoxyacetophenone (1d): Pale yellowish oil, Jꢂ3.0, 9.0 Hz, 4ꢀ-H), 6.975 (1H, d, Jꢂ9.0 Hz, 3ꢀ-H), 5.167 (2H, s, 5ꢀ-
Rfꢂ0.31 (benzene); IR (CHCl3) cmꢃ1: 1625 (CꢂO); 1H-NMR (300 MHz,
OCH2OCH3); 3.526 (3H, s, 5ꢀ-OCH2OCH3); HR-EI-MS m/z: 284.1048
CDCl3) d: 13.097 (1H, s, 2ꢀ-OH), 7.325 (1H, dd, Jꢂ8.0, 8.5 Hz, 4ꢀ-H), (Calcd for C17H16O4: 284.1049); Anal. Calcd for C17H16O4: C, 71.82, H,
2ꢀ-Hydroxy-5ꢀ-methoxymethoxychalcone (3c): Orange needles, Rfꢂ0.41
1

552
Vol. 53, No. 5
5.67; Found: C, 71.86, H, 5.77.
8.0 Hz, 7-H), 6.973 (1H, t, Jꢂ8.0 Hz, 6-H), 5.585 (1H, s, 8-OH), 5.525 (1H,
dd, Jꢂ3.0, 13.0 Hz, 2-H), 3.157 (1H, dd, Jꢂ13.0, 17.0 Hz, 3ax-H), 2.897
(1H, dd, Jꢂ3.0, 17.0 Hz, 3eq-H); HR-EI-MS m/z: 240.0805 (Calcd for
C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C, 74.99, H, 5.03; Found:
C, 74.88, H, 5.15.
6-Methoxymethoxyflavanone (4cꢀ): Colorless needles, Rfꢂ0.35 (ben-
zene); mp: 96—97 °C (EtOH), IR (CHCl3) cmꢃ1: 1683 (CꢂO); 1H-NMR
(400 MHz, CDCl3) d: 7.558 (1H, d, Jꢂ3.0 Hz, 5-H), 7.510—7.360 (5H, m,
2ꢀ,3ꢀ,4ꢀ,5ꢀ,6ꢀ-Hs), 7.223 (1H, dd, Jꢂ3.0, 9.0 Hz, 7-H), 7.006 (1H, d,
Jꢂ9.0 Hz, 8-H), 5.445 (1H, dd, Jꢂ3.0, 13.5 Hz, 2-H), 5.162 (2H, s, 6ꢀ-
OCH2OCH3), 3.487 (3H, s, 6ꢀ-OCH2OCH3), 3.068 (1H, dd, Jꢂ13.5,
17.0 Hz, 3ax-H), 2.883 (1H, dd, Jꢂ3.0, 17.0 Hz, 3eq-H); HR-EI-MS m/z:
284.1050 (Calcd for C17H16O4: 284.1049), Anal. Calcd for C17H16O4: C,
71.82, H, 5.67; Found: C, 71.77, H, 5.64.
2ꢀ-Hydroxy-6ꢀ-methoxymethoxychalcone (3d): Orange needles, Rfꢂ0.34
(benzene); mp: 52.5—53 °C (EtOH), IR (CHCl3) cmꢃ1: 1633 (CꢂO); 1H-
NMR (300 MHz, CDCl3) d: 12.863 (1H, s, 2ꢀ-OH), 7.907 (1H, d,
Jꢂ15.5 Hz, a-H), 7.815 (1H, d, Jꢂ15.5 Hz, b-H), 7.650—7.590 (2H, m,
2,6-Hs), 7.460—7.390 (3H, m, 3,4,5-Hs), 7.348 (1H, dd, Jꢂ8.0, 8.5 Hz, 4ꢀ-
H), 6.672 (1H, dd, Jꢂ1.0, 8.0 Hz, 3ꢀ-H), 6.613 (1H, dd, Jꢂ1.0, 8.5 Hz, 5ꢀ-
H), 5.310 (2H, s, 6ꢀ-OCH2OCH3), 3.535 (3H, s, 6ꢀ-OCH2OCH3); HR-EI-MS
m/z: 284.1039 (Calcd for C17H16O4: 284.1049), Anal. Calcd for C17H16O4: C,
71.82, H, 5.67; Found: C, 71.85, H, 5.83.
2ꢀ,3ꢀ-Dihydroxychalcone (3aꢀ): Red needles, Rfꢂ0.15 (n-hexane :
acetoneꢂ5 : 1); mp: 155 °C (EtOH) (lit.28) 151 °C); IR (CHCl3) cmꢃ1: 1640
1
(CꢂO); H-NMR (400 MHz, CDCl3) d: 13.102 (1H, d, Jꢂ0.5 Hz, 2ꢀ-OH),
7.946 (1H, d, Jꢂ15.5 Hz, b-H), 7.710—7.650 (2H, m, 2,6-Hs), 7.650 (1H, d,
Jꢂ15.5 Hz, a-H), 7.483 (1H, dd, Jꢂ1.5, 8.0 Hz, 6ꢀ-H), 7.480—7.425 (3H,
m, 3,4,5-Hs), 7.169 (1H, ddd, Jꢂ0.5, 1.5, 8.0 Hz, 4ꢀ-H), 6.877 (1H, t,
Jꢂ8.0 Hz, 5ꢀ-H), 5.801 (1H, s, 3ꢀ-OH); HR-EI-MS m/z: 240.0798 (Calcd for
C15H12O3: 240.0786), Anal. Calcd for C15H12O3: C, 74.99, H, 5.03; Found:
C, 74.89, H, 5.13.
7-Hydroxyflavanone (4b) To a solution of 2ꢀ-hydroxy-4ꢀ-methoxy-
methoxychalcone (3b, 50.2 mg, 0.18 mmol) in MeOH (1.0 ml), 25.8%
HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 2.5 h,
neutralized with a saturated NaHCO3 solution, and extracted with ethyl ac-
etate. The organic layer was extracted with water, dried over Na2SO4, and
evaporated. The residue was purified using preparative TLC (silica gel, ben-
zene : ethyl acetateꢂ20 : 1) to give 4b (30.3 mg, yield 71.4%) and 2ꢀ,4ꢀ-dihy-
droxychalcone (3bꢀ, 11.5 mg, 27.9%).
7-Hydroxyflavanone (4b): Colorless needles, Rfꢂ0.10 (benzene : ethyl ac-
etateꢂ20 : 1); mp: 194—197 °C (EtOH) (lit.29) 189—190 °C); IR (CHCl3)
cmꢃ1: 1678 (CꢂO); 1H-NMR (400 MHz, CDCl3) d: 7.863 (1H, d, Jꢂ9.0 Hz,
5-H), 7.490—7.360 (5H, m, 2ꢀ,3ꢀ,4ꢀ,5ꢀ,6ꢀ-Hs), 6.554 (1H, dd, Jꢂ2.0,
9.0 Hz, 6-H), 6.474 (1H, d, Jꢂ2.0 Hz, 8-H), 5.950 (1H, br, 7-OH), 5.467
(1H, dd, Jꢂ3.0, 13.0 Hz, 2-H), 3.049 (1H, dd, Jꢂ13.0, 17.0 Hz, 3ax-H),
2.843 (1H, dd, Jꢂ3.0, 17.0 Hz, 3eq-H); HR-EI-MS m/z: 240.0824 (Calcd for
C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C, 74.99, H, 5.03; Found:
C, 75.03, H, 5.19.
2ꢀ,4ꢀ-Dihydroxychalcone (3bꢀ): Yellow needles, Rfꢂ0.15 (benzene : ethyl
acetateꢂ20 : 1); mp: 148—152 °C (EtOH/n-hexane) (lit.29) 150 °C); IR
(CHCl3) cmꢃ1: 1635 (CꢂO); 1H-NMR (400 MHz, CDCl3) d: 13.365 (1H, s,
2ꢀ-OH), 7.889 (1H, d, Jꢂ15.5 Hz, b-H), 7.840 (1H, d, Jꢂ9.0 Hz, 6ꢀ-H),
7.670—7.635 (2H, m, 2,6-Hs), 7.575 (1H, d, Jꢂ15.5 Hz, a-H), 7.455—
7.415 (3H, m, 3,4,5-Hs), 6.440 (1H, dd, Jꢂ2.5, 9.0 Hz, 5ꢀ-H), 6.435 (1H, d,
Jꢂ2.5 Hz, 3ꢀ-H), 5.800 (1H, br, 4ꢀ-OH); HR-EI-MS m/z: 240.0795 (Calcd
for C15H12O3: 240.0786), Anal. Calcd for C15H12O3: C, 74.99, H, 5.03;
Found: C, 74.81, H, 5.24.
6-Hydroxyflavanone (4c) 1) To a solution of 2ꢀ-hydroxy-5ꢀ-methoxy-
methoxychalcone (3c, 51.2 mg, 0.18 mmol) in MeOH (1.0 ml), 17.8%
HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 1.0 h,
neutralized with a saturated NaHCO3 solution, and extracted with ethyl ac-
etate. The organic layer was extracted with water, dried over Na2SO4, and
evaporated. The residue was purified using preparative TLC (silica gel, ben-
zene : ethyl acetateꢂ10 : 1) to give 4c (39.4 mg, 91.1%) and 2ꢀ,5ꢀ-dihydroxy-
chalcone (3cꢀ, 3.8 mg, 8.8%).
2ꢀ-Hydroxy-2-methoxymethoxychalcone (3e)
A
mixture of 2-
methoxymethoxybenzaldehyde (2a, 50.2 mg, 0.30 mmol), 2ꢀ-hydroxyace-
tophenone (1, 40.8 mg, 0.30 mmol), and KOH (168.9 mg, 3.0 mmol) in
EtOH (5 ml) was stirred at room temperature for 23 h and then neutralized
by the addition of 10% AcOH in EtOH. This mixture was evaporated and
the residue was extracted with ethyl acetate. The organic layer was dried
over Na2SO4, and evaporated. The residue was purified using preparative
TLC (benzene : n-hexaneꢂ2 : 1) to give 3e (69.2 mg, yield 81.2%) as a yel-
low oil. Rfꢂ0.31 (benzene : hexaneꢂ2 : 1); IR (CHCl3) cmꢃ1: 1632 (CꢂO);
1H-NMR (400 MHz, CDCl3) d: 12.910 (1H, s, 2ꢀ-OH), 8.300 (1H, d,
Jꢂ15.5 Hz, b-H), 7.930 (1H, dd, Jꢂ1.5, 8.0 Hz, 6ꢀ-H), 7.752 (1H, d,
Jꢂ15.5 Hz, a-H), 7.696 (1H, dd, Jꢂ2.0, 7.5 Hz, 6-H), 7.501 (1H, ddd,
Jꢂ1.5, 7.5, 8.0 Hz, 4ꢀ-H), 7.388 (1H, ddd, Jꢂ2.0, 7.5, 8.0 Hz, 4-H), 7.202
(1H, dd, Jꢂ1.0, 8.0 Hz, 3-H), 7.073 (1H, dt, Jꢂ1.0, 7.5 Hz, 5-H), 7.035 (1H,
dd, Jꢂ1.0, 8.0 Hz, 3ꢀ-H), 6.950 (1H, ddd, Jꢂ1.0, 7.5, 8.0 Hz, 5ꢀ-H), 5.313
(2H, s, 2-OCH2OCH3), 3.530 (3H, s, 2-OCH2OCH3); HR-EI-MS m/z:
284.1044 (Calcd for C17H16O4: 284.1049), Anal. Calcd for C17H16O4: C,
71.82, H, 5.67; Found: C, 71.70, H, 5.74.
2ꢀ-Hydroxy-3-methoxymethoxychalcone (3f) and 2ꢀ-Hydroxy-4-
methoxymethoxychalcone (3g) Compounds 3f and 3g were prepared
starting with the corresponding monohydroxybenzaldehydes (2b, c) using
procedures similar to that described for preparation of 3e.
2ꢀ-Hydroxy-3-methoxymethoxychalcone (3f): Yellow needles, Rfꢂ0.39
(benzene); mp: 78—78.5 °C (EtOH); IR (CHCl3) cmꢃ1: 1639 (CꢂO); 1H-
NMR (400 MHz, CDCl3) d: 12.794 (1H, s, 2ꢀ-OH), 7.928 (1H, dd, Jꢂ1.5,
8.0 Hz, 6ꢀ-H), 7.888 (1H, d, Jꢂ15.5 Hz, b-H), 7.640 (1H, d, Jꢂ15.5 Hz, a-
H), 7.510 (1H, ddd, Jꢂ1.5, 7.5, 8.0 Hz, 4ꢀ-H), 7.362 (1H, dd, Jꢂ7.5, 8.5 Hz,
5-H), 7.335 (1H, dd, Jꢂ1.5, 2.5 Hz, 2-H), 7.315 (1H, ddd, Jꢂ1.0, 1.5,
7.5 Hz, 6-H), 7.128 (1H, ddd, Jꢂ1.0, 2.5, 8.5 Hz, 4-H), 7.036 (1H, dd,
Jꢂ1.0, 8.0 Hz, 3ꢀ-H), 6.956 (1H, ddd, Jꢂ1.0, 7.5, 8.0 Hz, 5ꢀ-H), 5.234 (2H,
s, 3-OCH2OCH3), 3.514 (3H, s, 3-OCH2OCH3); HR-EI-MS m/z: 284.1049
(Calcd for C17H16O4: 284.1049), Anal. Calcd for C17H16O4: C, 71.82, H,
5.67; Found: C, 71.65, H, 5.79.
2ꢀ-Hydroxy-4-methoxymethoxychalcone (3g): Yellow oil, Rfꢂ0.36 (ben-
zene); IR (CHCl3) cmꢃ1: 1640 (CꢂO); 1H-NMR (400 MHz, CDCl3) d:
12.906 (1H, s, 2ꢀ-OH), 7.924 (1H, dd, Jꢂ1.5, 8.0 Hz, 6ꢀ-H), 7.904 (1H, d,
Jꢂ15.5 Hz, b-H), 7.628 (2H, d, Jꢂ9.0 Hz, 2,6-Hs), 7.558 (1H, d,
Jꢂ15.5 Hz, a-H), 7.495 (1H, ddd, Jꢂ1.5, 7.5, 8.5 Hz, 4ꢀ-H), 7.094 (2H, d,
Jꢂ9.0 Hz, 3,5-Hs), 7.027 (1H, dd, Jꢂ1.0, 8.5 Hz, 3ꢀ-H), 6.944 (1H, ddd,
Jꢂ1.0, 7.5, 8.0 Hz, 5ꢀ-H), 5.233 (2H, s, 4-OCH2OCH3), 3.497 (3H, s, 4-
OCH2OCH3); HR-EI-MS m/z: 284.1040 (Calcd for C17H16O4: 284.1049),
Anal. Calcd for C17H16O4: C, 71.82, H, 5.67; Found: C, 71.70, H, 5.81.
8-Hydroxyflavanone (4a) To a solution of 2ꢀ-hydroxy-3ꢀ-methoxy-
methoxychalcone (3a, 55.6 mg, 0.20 mmol) in MeOH (2.0 ml), 25.8%
HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 2.0 h,
neutralized with a saturated NaHCO3 solution and extracted with ethyl ac-
etate. The organic layer was extracted with water, dried over Na2SO4, and
evaporated. The residue was purified using preparative TLC (silica gel, ben-
zene : ethyl acetateꢂ20 : 1) to give 4a (34.8 mg, yield 74.1%). In the same
manner, the residue was purified using preparative TLC (silica gel, n-
hexane : acetoneꢂ5 : 1) to give a trace of 2ꢀ,3ꢀ-dihydroxychalcone 3aꢀ.
8-Hydroxyflavanone (4a): Colorless needles, Rfꢂ0.08 (n-hexane : ace-
toneꢂ5 : 1); mp: 204 °C (EtOH) (lit.28) 192 °C); IR (CHCl3) cmꢃ1: 1690
(CꢂO); 1H-NMR (300 MHz, CDCl3) d: 7.570—7.420 (5H, m,
2ꢀ,3ꢀ,4ꢀ,5ꢀ,6ꢀ-Hs); 7.485 (1H, dd, Jꢂ1.5, 8.0 Hz, 5-H), 7.163 (1H, dd, Jꢂ1.5,
2) To
a solution of 6-methoxymethoxyflavanone (4cꢀ, 33.1 mg,
0.12 mmol) in MeOH (0.5 ml), 12.0% HCl–MeOH (0.5 ml) was added. The
mixture was stirred at room temperature for 0.5 h, after which an additional
0.5 ml of 12.0% HCl–MeOH was added. The mixture was stirred at 50 °C
for an additional 0.5 h, then neutralized with a saturated NaHCO3 solution,
and extracted with ethyl acetate. The organic layer was extracted with water,
dried over Na2SO4, and evaporated. The residue was purified using prepara-
tive TLC (silica gel, benzene : ethyl acetateꢂ10 : 1) to give 4c (28.4 mg,
yield 95.8%).
6-Hydroxyflavanone (4c): Pale yellowish needles, Rfꢂ0.11
(benzene : ethyl acetateꢂ20 : 1); mp: 225 °C (EtOH) (lit.23) 220 °C); IR
1
(CHCl3) cmꢃ1: 1685 (CꢂO); H-NMR (400 MHz, CDCl3) d: 7.500—7.350
(5H, m, 2ꢀ,3ꢀ,4ꢀ,5ꢀ,6ꢀ-Hs), 7.328 (1H, d, Jꢂ3.0 Hz, 5-H), 7.075 (1H, dd,
Jꢂ3.0, 9.0 Hz, 7-H), 6.975 (1H, d, Jꢂ9.0 Hz, 8-H), 5.436 (1H, dd, Jꢂ3.0,
13.5 Hz, 2-H), 4.982 (1H, br, 6-OH), 3.065 (1H, dd, Jꢂ13.5, 17.5 Hz, 3ax-
H), 2.873 (1H, dd, Jꢂ3.0, 17.5 Hz, 3eq-H); HR-EI-MS m/z: 240.0809
(Calcd for C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C, 74.99, H,
5.03; Found: C, 75.01, H, 5.18.
2ꢀ,5ꢀ-Dihydroxychalcone (3cꢀ): Orange needles, Rfꢂ0.18 (benzene : ethyl
acetateꢂ20 : 1); mp: 179—180 °C (EtOH) (lit.23) 170 °C); IR (CHCl3) cmꢃ1
:
1
1642 (CꢂO); H-NMR (400 MHz, CDCl3) d: 12.346 (1H, s, 2ꢀ-OH), 7.915
(1H, d, Jꢂ15.5 Hz, b-H), 7.685—7.640 (2H, m, 2,6-Hs), 7.582 (1H, d,
Jꢂ15.5 Hz, a-H), 7.460—7.430 (3H, m, 3,4,5-Hs), 7.390 (1H, d, Jꢂ3.0 Hz,
6ꢀ-H), 7.062 (1H, dd, Jꢂ3.0, 9.0 Hz, 4ꢀ-H), 6.937 (1H, d, Jꢂ9.0 Hz, 3ꢀ-H),
4.900 (1H, br, 5ꢀ-OH); HR-EI-MS m/z: 240.0800 (Calcd for C15H12O3:
240.0786), Anal. Calcd for C15H12O3: C, 74.99, H, 5.03; Found: C, 74.95, H,

May 2005
5.27.
553
240.0786); Anal. Calcd for C15H12O3: C, 74.99, H, 5.03; Found: C, 74.80, H,
5-Hydroxyflavanone (4d) To a solution of 2ꢀ-hydroxy-6ꢀ-methoxy- 5.31.
methoxychalcone (3d, 2.2771 g, 8.0 mmol) in MeOH (10.0 ml), 17.8%
4ꢀ-Hydroxyflavanone (4g) To a solution of 2ꢀ-hydroxy-4-methoxy-
methoxychalcone (3g, 50.0 mg, 0.18 mmol) in MeOH (1.0 ml), 17.8%
HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 3.5 h,
neutralized with a saturated NaHCO3 solution, and extracted with ethyl ac- HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 1.0 h,
etate. The organic layer was extracted with water, dried over Na2SO4, and neutralized with a saturated NaHCO3 solution, and extracted with ethyl ac-
evaporated. The residue was chromatographed over a column of silica gel in
etate. The organic layer was extracted with water, dried over Na2SO4, and
evaporated. The residue was purified using preparative TLC (silica gel, ben-
benzene to purify 4d (1.5825 g, yield 82.2%) as a colorless needles.
Rfꢂ0.55 (benzene); mp: 64.5—65 °C (EtOH) (lit.30) 62—63 °C); IR (CHCl3) zene : ethyl acetateꢂ20 : 1) to give 4g (26.7 mg, yield 63.2%) and 2ꢀ,4-dihy-
1
cmꢃ1: 1640 (CꢂO); H-NMR (400 MHz, CDCl3) d: 11.682 (1H, s, 5-OH),
7.490—7.360 (5H, m, 2ꢀ,3ꢀ,4ꢀ,5ꢀ,6ꢀ-Hs), 7.390 (1H, dd, Jꢂ8.0, 8.5 Hz, 7-
H), 6.547 (1H, dd, Jꢂ1.0, 8.5 Hz, 6-H), 6.517 (1H, dd, Jꢂ1.0, 8.0 Hz, 8-H),
droxychalcone (3gꢀ, 14.5 mg, yield 34.3%).
4ꢀ-Hydroxyflavanone (4g): Colorless needles, Rfꢂ0.12 (benzene : ethyl
acetateꢂ20 : 1); mp: 191 °C (EtOH) (lit.33) 189—190 °C); IR (CHCl3) cmꢃ1
:
1
5.465 (1H, dd, Jꢂ3.0, 13.0 Hz, 2-H), 3.151 (1H, dd, Jꢂ13.0, 17.5 Hz, 3ax- 1690 (CꢂO); H-NMR (400 MHz, CDCl3) d: 7.932 (1H, ddd, Jꢂ0.5, 2.0,
H), 2.898 (1H, dd, Jꢂ3.0, 17.5 Hz, 3eq-H); HR-EI-MS m/z: 240.0800 8.0 Hz, 5-H), 7.506 (1H, ddd, Jꢂ2.0, 7.0, 8.5 Hz, 7-H), 7.368 (2H, d,
(Calcd for C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C, 74.99, H, Jꢂ9.0 Hz, 2ꢀ,6ꢀ-Hs), 7.050 (1H, ddd, Jꢂ1.0, 7.0, 8.0 Hz, 6-H), 7.038 (1H,
5.03; Found: C, 74.79, H, 5.02.
ddd, Jꢂ0.5, 1.0, 8.5 Hz, 8-H), 6.895 (2H, d, Jꢂ9.0 Hz, 3ꢀ,5ꢀ-Hs), 5.424 (1H,
2ꢀ-Hydroxyflavanone (4e) To a solution of 2ꢀ-hydroxy-2-methoxy- dd, Jꢂ3.0, 13.5 Hz, 2-H), 5.120 (1H, br, 4ꢀ-OH), 3.100 (1H, dd, Jꢂ13.5,
methoxychalcone (3e, 68.7 mg, 0.24 mmol) in MeOH (4.0 ml), 17.8%
HCl–MeOH (0.1 ml) was added. The mixture was stirred at 100 °C for
15 min, neutralized with a saturated NaHCO3 solution, and extracted with
ethyl acetate. The organic layer was extracted with water, dried over Na2SO4,
and evaporated. The residue was purified using preparative TLC (silica gel,
17.5 Hz, 3ax-H), 2.864 (1H, dd, Jꢂ3.0, 17.5 Hz, 3eq-H); HR-EI-MS m/z:
240.0809 (Calcd for C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C,
74.99, H, 5.03; Found: C, 74.72, H, 5.04.
2ꢀ,4-Dihydroxychalcone (3gꢀ): Orange needles, Rfꢂ0.17 (benzene : ethyl
acetateꢂ20 : 1); mp: 167 °C (EtOH) (lit.33) 157—158 °C); IR (CHCl3) cmꢃ1
:
1
benzene) to give 4e (38.3 mg, yield 66.0%) and 2,2ꢀ-dihydroxychalcone 1637 (CꢂO); H-NMR (400 MHz, CDCl3) d: 12.925 (1H, s, 2ꢀ-OH), 7.922
(3eꢀ, 14.4 mg, yield 24.8%).
(1H, dd, Jꢂ1.5, 8.0 Hz, 6ꢀ-H), 7.894 (1H, d, Jꢂ15.5 Hz, b-H), 7.595 (2H, d,
Jꢂ9.0 Hz, 2,6-Hs), 7.540 (1H, d, Jꢂ15.5 Hz, a-H), 7.494 (1H, ddd, Jꢂ1.5,
2ꢀ-Hydroxyflavanone (4e): Colorless needles, Rfꢂ0.14 (benzene : ethyl
acetateꢂ20 : 1); mp: 170 °C (EtOH) (lit.31) 165—165.5 °C); IR (CHCl3) 7.5, 8.5 Hz, 4ꢀ-H), 7.028 (1H, dd, Jꢂ1.0, 8.5 Hz, 3ꢀ-H), 6.942 (1H, ddd,
cmꢃ1: 1690 (CꢂO); 1H-NMR (400 MHz, CDCl3) d: 7.968 (1H, ddd, Jꢂ0.5,
2.0, 8.0 Hz, 5-H), 7.537 (1H, ddd, Jꢂ2.0, 7.0, 8.5 Hz, 7-H), 7.363 (1H, dd, Jꢂ1.0, 2.0, 8.0 Hz, 6-H), 7.140 (1H, dd, Jꢂ2.0, 2.5 Hz, 2-H), 6.923 (1H,
Jꢂ1.5, 7.5 Hz, 6ꢀ-H), 7.270 (1H, ddd, Jꢂ1.5, 8.0, 8.5 Hz, 4ꢀ-H), 7.102 (1H, ddd, Jꢂ1.0, 2.5, 8.0 Hz, 4-H), 5.430 (1H, br, 4-OH); HR-EI-MS m/z:
Jꢂ1.0, 7.5, 8.0 Hz, 5ꢀ-H), 7.313 (1H, t, Jꢂ8.0 Hz, 5-H), 7.243 (1H, ddd,
ddd, Jꢂ1.0, 7.0, 8.0 Hz, 6-H), 7.088 (1H, ddd, Jꢂ0.5, 1.0, 8.5 Hz, 8-H), 240.0770 (Calcd for C15H12O3: 240.0786); Anal. Calcd for C15H12O3: C,
6.990 (1H, ddd, Jꢂ1.0, 7.5, 8.5 Hz, 5ꢀ-H), 6.918 (1H, dd, Jꢂ1.0, 8.0 Hz, 3ꢀ- 74.99, H, 5.03; Found: C, 74.80, H, 5.31.
H), 6.268 (1H, br, 2ꢀ-OH), 5.778 (1H, dd, Jꢂ3.0, 13.0 Hz, 2-H), 3.156 (1H,
dd, Jꢂ13.0, 17.0 Hz, 3ax-H), 3.022 (1H, dd, Jꢂ3.0, 17.0 Hz, 3eq-H); HR-
EI-MS m/z: 240.0793 (Calcd for C15H12O3: 240.0786); Anal. Calcd for
C15H12O3: C, 74.99, H, 5.03; Found: C, 74.75, H, 5.14.
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:
1
1632 (CꢂO); H-NMR (400 MHz, CDCl3) d: 12.914 (1H, s, 2ꢀ-OH), 8.188
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methoxychalcone (3f, 56.7 mg, 0.20 mmol) in MeOH (1.0 ml), 17.8%
HCl–MeOH (2.0 ml) was added. The mixture was stirred at 100 °C for 1 h,
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1
cmꢃ1: 1685 (CꢂO); H-NMR (400 MHz, CDCl3) d: 7.933 (1H, dd, Jꢂ2.0,
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