Total Syntheses of 4′,6′-Dimethoxy-2'-Hydroxy-3′,5′-Dimethylchalcone Derivatives

Article abstract of DOI:10.1002/bkcs.12156

Chalcone derivatives afford several pharmacological activities. However, a general synthetic method for 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) derivatives has not been reported thus far. To address this, the preparation of 4',6'-dimethoxy-2'-hydroxy-3',5'-dimethylchalcone (MDMC) derivatives, modified compounds of DMC, in excellent overall yields is reported herein. These compounds have recently attracted growing attention due to their various pharmacological activities. Di-O-methyl-dimethylphloroacetophenone, the key intermediate containing the B-ring moiety, was fabricated by four efficient reaction steps from commercially available phloroglucinol in a 50.1% isolated yield overall. Our synthetic route, which constructs the chalcone skeleton in the final stage via a Claisen–Schmidt condensation of the key intermediate with the desired benzaldehyde derivative, can rapidly produce a vast library of DMC derivatives.

Full text of DOI:10.1002/bkcs.12156

Article
DOI: 10.1002/bkcs.12156
BULLETIN OF THE
H. Lee et al.
KOREAN CHEMICAL SOCIETY
Total Syntheses of 40,60-Dimethoxy-2’-Hydroxy-30,50-Dimethylchalcone
Derivatives
*
Hana Lee, Rae Yeon Park, and Kwangyong Park
School of Chemical Engineering and Material Science, Chung-Ang University, 84 Heukseok-ro, Dongjak-
gu, Seoul 06974, Republic of Korea. *E-mail: kypark@cau.ac.kr
Received November 6, 2020, Accepted November 10, 2020
Chalcone derivatives afford several pharmacological activities. However, a general synthetic method for
2’,4’-dihydroxy-6’-methoxy-3’,5’-dimethylchalcone (DMC) derivatives has not been reported thus far. To
address this, the preparation of 4’,6’-dimethoxy-2’-hydroxy-3’,5’-dimethylchalcone (MDMC) derivatives,
modified compounds of DMC, in excellent overall yields is reported herein. These compounds have
recently attracted growing attention due to their various pharmacological activities. Di-O-methyl-
dimethylphloroacetophenone, the key intermediate containing the B-ring moiety, was fabricated by four
efficient reaction steps from commercially available phloroglucinol in a 50.1% isolated yield overall. Our
synthetic route, which constructs the chalcone skeleton in the final stage via a Claisen–Schmidt condensa-
tion of the key intermediate with the desired benzaldehyde derivative, can rapidly produce a vast library
of DMC derivatives.
Keywords: Total synthesis, 4’,60-dimethoxy-2’-hydroxy-3’,5’-dimethylchalcone, Phloroglucinol,
Claisen–Schmidt condensation, Benzaldehyde
Introduction
tune its structure by modifying the substituents on the B and
A rings, while retaining the key five functionalities present
on the B ring, namely the alternatively attached three
hydroxy/alkoxy groups and the two methyl groups
(Figure 1).
Considering that a large amount of bioactive compounds
should be examined to characterize the various biological activ-
ities of such structures, an appropriate synthetic method capable
of rapidly producing the desired compounds in large quantities
is necessary. Although various methods have been developed
for the preparation of chalcones,36,37 a general synthetic method
for DMC derivatives is yet to be reported, presumably because
the regioselective arrangement of the three hydroxy/alkoxy
groups and the two alkyl groups on the B-ring is challenging.
Thus, we herein report an efficient total synthesis for 40,60-
dimethoxy-20-hydroxy-30,50-dimethylchalcone (MDMC, 2)
derivatives starting from affordable phloroglucinol.
Chalcone derivatives bearing a scaffold composed of two
benzene moieties connected by an α,β-unsaturated carbonyl
bridge are known to exhibit a wide range of pharmacologi-
cal activities.1–4 In addition, they have been used as impor-
tant precursors for a variety of new drug candidates,
including flavonoids and isoflavonoids.5–7 It is well-known
that the pharmacological activity of a compound is greatly
influenced not only by the basic skeleton of the compound
but also by the electronic property and size of functional
groups attached to the skeleton. As we may expect,
the pharmacological activities of chalcone compounds are
dependent on the functionalities of the two phenyl
rings.8–15 Indeed, we recently disclosed that the antidiabetic
activity of 2’,4’,6’-trihydroxychalcone derivatives was
largely dependent on the substituents present on the phenyl
rings.16 Thus, the syntheses of systematically designed
chalcone derivatives could be considered necessary to
understand the structure–activity relationship of the
chalcones and ultimately lead to promising new drug
candidates.
Experimental
General Information. N,N-Dimethylformamide (DMF),
phloroglucinol, boron trifluoride diethyl etherate,
20,40-Dihydroxy-60-methoxy-30,50-dimethylchalcone (DMC,
1), a highly substituted chalcone extracted from many
natural plants17–21 has recently attracted growing
attention due to its various pharmacological activities,
including anti-tumor,22–25 antivirus,26 anti-oxidative,27,28
anti-inflammatory,29,30 hepatoprotective,31,32 and anti-
diabetic effects.33–35 During our studies into the optimization
of the specific pharmacological activity of 1, we planned to
4-fluorobenzaldehyde,
4-hydroxybenzaldehyde,
and
4-methoxybenzaldehyde were purchased from Alfa Aesar
(Ward Hill, MA). Mercury(II) chloride and zinc powder
was purchased from Samchun Chemicals (Seoul, Republic of
Korea). Dimethyl sulfate, benzaldehyde and p-toluenesulfonic
acid were purchased from Sigma–Aldrich Co. (St. Louis,
MO). 4-Methylbenzaldehyde and 4-isopropylbenzaldehyde
were purchased from Acros Orgacins (Morris Plains, NJ).
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5.90 (s, 1H, Ar H); 13C NMR (DMSO‑d6, 150 MHz) δ
191.4 (2C), 169.4 (2C), 169.0 (1C), 103.8 (2C), 94.1 (1C).
Synthesis of 2,4-dimethylphloroglucinol (4). Zinc pow-
der (30.0 g) that had been activated by stirring in a 1% HCl
aqueous solution (300 mL) was added to a 3% HCl aque-
ous solution (450 mL). Mercury(II) chloride (0.900 g) was
then added, and the resulting mixture was stirred vigorously
at 25ꢀC for 4 h. The obtained fluffy solid was washed with
water and 1,4-dioxane, filtered, and added to a solution of
5 (3.00 g, 16.5 mmol) in 1,4-dioxane (300 mL). The reac-
tion mixture was stirred at 25ꢀC for 20 min and then cooled
to 0 ꢀC. Subsequently, a 36% HCl aqueous solution
(12 mL) was added slowly, and the mixture was stirred for
30 min. After this time, the reaction mixture was filtered,
washed with water (200 mL), and extracted with ethyl ace-
tate (EtOAc, 3 × 100 mL). The combined organic layer
was washed with saturated NaCl aqueous solution and
dried over anhydrous MgSO4. The organic solvent was
evaporated under reduced pressure, and the crude product
was purified via column chromatography (n-hexane: ace-
Figure 1. Structures of DMC (1) and the MDMC derivatives (2).
Phosphorus oxychloride was purchased from Daejung
chemicals (Gyeonggi-do, Republic of Korea). Chloromethyl
methyl ether was purchased from Kanto Chemical Co., Inc.
(Tokyo, Japan). 4-Methoxymethoxybenzaldehyde was prepared
as previously described.38
Acetone was dehydrated using 4 Å molecular sieves
prior to use. Analytical thin-layer chromatography (TLC)
was performed using Merck Kieselgel 60 F254 precoated
plates (0.25 mm) with a fluorescent indicator and visualized
either under UV light (254 and 365 nm) or by iodine
staining. Column chromatography was performed on silica
gel 60 (70–230 mesh; Merck, Darmstadt, Germany). Gas
chromatography (GC) was performed on a bonded 5% phe-
nyl polysiloxane BPX five-capillary column (SGE, 30 m,
0.32 mm i.d.) using a GC system (HP 6890 series; Hewlett-
Packard, Palo Alto, CA). 1H NMR (600 MHz) and 13C
NMR (150 MHz) spectra were acquired on a 600-MHz
spectrometer (VNS, Varian, Palo Alto, CA) using
tone = 8:1) to afford 4 (1.72 g, 11.2 mmol, 67.9%) as a
41
ꢀ
brown powder: mp 162–163ꢀC (lit. mp 158–16 C); TLC
Rf = 0.67 (n-hexane:acetone = 1:2); IR νmax (cm−1) 3527,
3465, 3425, 2921, 2852, 1609, 1457, 1433, 1247, 1150; H
1
NMR (DMSO‑d6, 300 MHz) δ 8.62 (s, 2H, OH), 7.76 (s,
1H, OH), 5.92 (s, 1H, Ar H), 1.86 (s, 6H, CH3); 13C
NMR (DMSO‑d6, 150 MHz) δ 154.1 (2C), 153.2 (2C),
102.6 (1C), 94.6 (1C), 8.7 (2C).
1
DMSO‑d6 or CDCl3 as the solvent. H NMR (300 MHz)
spectra were acquired on
a 300-MHz spectrometer
(Germini 2000, Varian, Palo Alto, CA) using DMSO‑d6 as
a solvent. The chemical shifts were referenced to the resid-
ual solvent peaks (δH 2.50 and δC 39.5 for DMSO‑d6 in
Synthesis of 2,4,6-trimethoxy-3,5-dimethylbenzene (6).
To a suspension of 4 (1.72 g, 11.2 mmol) and K2CO3
(6.16 g, 44.6 mmol) in dry acetone (30 mL), dimethyl sul-
fate (4.22 mL, 44.5 mmol) was added under a N2 atmo-
sphere. The reaction mixture was stirred at reflux overnight
and then cooled to room temperature. The reaction mixture
was diluted with EtOAc (300 mL) and acidified with a 1%
HCl aqueous solution (300 mL). The organic layer was sep-
arated, washed with water (3 × 300 mL) and saturated
NaCl aqueous solution (300 mL), and dried over anhydrous
MgSO4. The organic solvent was then evaporated under
reduced pressure, and the crude product was purified via
column chromatography (n-hexane:acetone = 300:1) to
afford 6 (2.16 g, 11.0 mmol, 98.2%) as a white powder:
mp 52–55ꢀC (lit.41 mp 46–48ꢀC); TLC Rf = 0.69 (n-hex-
ane:acetone = 3:2); IR νmax (cm−1) 2926, 1608, 1496,
1464, 1435, 1401, 1321, 1219, 1193, 1127; 1H NMR
(DMSO‑d6, 300 MHz) δ 6.41 (s, 1H, Ar H), 3.77 (s, 6H,
OCH3), 3.57 (s, 3H, OCH3), 1.98 (s, 6H, CH3); 13C
NMR (DMSO‑d6, 150 MHz) δ 157.2 (1C), 156.3 (2C),
109.9 (2C), 91.8 (1C), 59.7 (1C), 55.5 (2C), 8.5 (2C).
1
the H NMR and 13C NMR spectra, respectively). All cou-
pling constants, J, are reported in hertz (Hz). Melting points
were measured using a melting point apparatus (Barnstead
Electrothermal 9100, Cole-Palmer Ltd., Stone, UK; 15 V,
45 W, 1 A).
Synthesis of 2,4-diformylphloroglucinol (5). Phosphorus
oxychloride (59.3 mL, 0.636 mol) was added dropwise to
DMF (49.1 mL, 0.636 mol) with stirring at 0 ꢀC. After
complete addition, the mixture was vigorously stirred for
30 min at 25ꢀC. The resulting yellow viscous liquid
(Vilsmeier reagent) was added dropwise to a solution of
anhydrous phloroglucinol (40.0 g,ꢀ 0.317 mol) in
1,4-dioxane (200 mL) with stirring at 0 C. After vigorous
stirring for 4 h at 25ꢀC, the resulting yellow amorphous
solid was transferred to a 2 L round-bottom flask using
water (1.5 L), and vigorously stirred for 3 h at 25ꢀC. The
precipitated yellow solid was filtered, washed with water,
and dried in a vacuum oven for 12 h at 30ꢀC to afford
5 (56.8 g, 0.312 mol, 98.4%). The crude product was suffi-
ciently pure for use in the next step without further purifica-
tion: mp 221–224ꢀC (lit.39,40 mp >220ꢀC); TLC Rf = 0.21
(n-hexane: acetone = 1:2); IR νmax (cm−1) 2888, 1599,
1503, 1439, 1393, 1254, 1187; 1H NMR (DMSO‑d6,
300 MHz) δ 12.52 (br s, 2H, OH), 10.01 (s, 2H, CHO),
Synthesis
3,5-dimethylacetophenone (3).
of
2-hydroxy-4,6-dimethoxy-
Acetic anhydride
(2.07 mL, 22.0 mmol) was added to 6 (2.16 g, 11.0 mmol)
ꢀ
under a N2 atmosphere. The solution was cooled at 0 C,
and BF3ꢁEt2O (2.76 mL, 22.4 mmol) was added to the solu-
tion by syringe. After stirring for 3 h at 90ꢀC, the reaction
mixture was diluted with EtOAc (300 mL), acidified with a
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Article Total Syntheses of 4’,6’-Dimethoxy-2’-Hydroxy-3’,5’-Dimethylchalcone Derivatives KOREAN CHEMICAL SOCIETY
1% HCl aqueous solution (300 mL), washed with water
(3 × 300 mL) and saturated NaCl aqueous solution
(300 mL), and then dried over anhydrous MgSO4. The
organic solvent was evaporated under reduced pressure,
and the crude product was purified via column chromatog-
raphy using n-hexane as an eluent to afford 3 (1.88 g,
8.39 mmol, 76.3%) as a yellow powder: mp 48–50ꢀC (lit.41
mp 49–51ꢀC); TLC Rf = 0.66 (n-hexane:acetone = 3:2); IR
νmax (cm−1) 3440, 2941, 1621, 1454, 1417, 1364, 1318,
purified via column chromatography to afford 2b (0.650 g,
2.08 mmol, 93.3%) as a pale orange solid: mp 138–140ꢀC;
TLC Rf = 0.58 (n-hexane:acetone = 3:2); IR νmax (cm−1
)
3369, 2924, 1627, 1606, 1553, 1512, 1348, 1261, 1141,
1
1108, 1023; H NMR (DMSO‑d6, 300 MHz) δ 12.05 (s,
1H, OH), 7.73 (m, 2H, Ar H), 7.71 (t, J = 18.16 Hz, 2H,
C C H), 7.45 (m, 3H, Ar − H), 3.70 (s, 3H, OCH3),
3.62 (s, 3H, OCH3), 2.11 (s, 3H, CH3), 2.07 (s, 3H,
CH3); 13C NMR (DMSO‑d6, 150 MHz) δ 193.8 (1C),
162.2 (1C), 158.4 (1C), 157.4 (1C), 143.6 (1C), 134.6
(1C), 130.7 (1C), 129.1 (2C), 128.5 (2C), 126.8 (1C),
115.5 (1C), 114.7 (1C), 113.4 (1C), 62.0 (1C), 59.9 (1C),
8.8 (1C), 8.7 (1C).
1
1283, 1198, 1171, 1120; H NMR (DMSO‑d6, 300 MHz)
δ 12.80 (s, 1H, OH), 3.71 (s, 3H, OCH3), 3.69 (s, 3H,
OCH3), 2.65 (s, 3H, COCH3), 2.09 (s, 3H, CH3),
2.03 (s, 3H, CH3); 13C NMR (DMSO‑d6, 150 MHz) δ
204.3 (1C), 162.8 (1C), 159.4 (1C), 158.4 (1C), 115.1
(1C), 114.4 (1C), 112.3 (1C), 61.5 (1C), 59.8 (1C), 31.5
(1C), 9.0 (1C), 8.5 (1C).
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-3-p-
tolyl-2-propen-1-one (2c). To a solution of 3 (0.500 g,
2.23 mmol) and p-tolualdehyde (0.316 mL, 2.68 mmol) in
MeOH (20 mL), KOH (0.375 g, 6.68 mmol) in MeOH
(10 mL) was added. The crude product was purified via
column chromatography to afford 2c (0.651 g, 2.00 mmol,
89.7%) as a pale orange solid: mp 83–85ꢀC; TLC Rf = 0.74
(n-hexane:acetone = 3:2); IR νmax (cm−1) 3513, 2962,
1630, 1560, 1412, 1344, 1261, 1141, 1109, 1019; 1H NMR
(DMSO‑d6, 300 MHz) δ 12.12 (s, 1H, OH), 7.67 (t,
J = 16.97 Hz, J = 17.06 Hz, 2H, C C H), 7.63 (d,
J = 7.85 Hz, 2H, Ar H), 7.27 (d, J = 7.85 Hz, 2H, Ar H),
3.70 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 2.35 (s, 3H,
CH3), 2.11 (s, 3H, CH3), 2.06 (s, 3H, CH3); 13C
NMR (DMSO‑d6, 150 MHz) δ 193.7 (1C), 162.1 (1C),
158.5 (1C), 157.4 (1C), 143.7 (1C), 140.8 (1C), 131.9
(1C), 129.7 (2C), 128.6 (2C), 125.8 (1C), 115.2 (1C),
114.7 (1C), 113.4 (1C), 61.9 (1C), 59.9 (1C), 21.1 (1C),
8.8 (1C), 8.7 (1C).
General synthetic route to MDMC derivatives (2). To a
solution of 3 (2.23 mmol) in MeOH (20 mL), the desired
benzaldehyde (2.68 mmol) was added. KOH (6.69 mmol)
predissolved in MeOH with the aid of sonication was then
added, and the reaction mixture was stirred for 48 h at
25ꢀC. After this time, the obtained mixture was diluted
with EtOAc (150 mL), acidified with a 1 M NH4Cl aque-
ous solution (100 mL), washed with water (3 × 200 mL)
and saturated NaCl aqueous solution (200 mL), and then
dried over anhydrous MgSO4. The organic solvent was
evaporated under reduced pressure, and the crude product
was purified via column chromatography (n-hexane to
remove any unreacted aldehyde, then n-hexane:
acetone = 300:1).
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-
3-(4-fluorophenyl)-2-propen-1-one (2a). To a solution of
3
(0.500 g, 2.23 mmol) and 4-fluorobenzaldehyde
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-
3-(4-isopropylphenyl)-2-propen-1-one (2d). To a solution
of 3 (0.500 g, 2.23 mmol) and 4-isopropylbenzaldehyde
(0.405 mL, 2.67 mmol) in MeOH (20 mL), KOH (0.375 g,
6.68 mmol) in MeOH (10 mL) was added. The crude prod-
uct was purified via column chromatography to afford 2d
(0.730 g, 2.06 mmol, 92.4%) as a pale orange solid: mp
76–78ꢀC; TLC Rf = 0.74 (n-hexane:acetone = 3:2); IR νmax
(cm−1) 3535, 2960, 1630, 1560, 1458, 1416, 1344, 1280,
1194, 1142, 1111; 1H NMR (DMSO‑d6, 300 MHz) δ
(0.283 mL, 2.64 mmol) in MeOH (20 mL), KOH (0.375 g,
6.68 mmol) in MeOH (10 mL) was added. The crude prod-
uct was purified via column chromatography to afford 2a
(0.664 g, 2.01 mmol, 90.1%) as a pale orange solid: mp
89–91ꢀC; TLC Rf = 0.71 (n-hexane:acetone = 3:2); IR νmax
(cm−1) 3447, 2941, 1629, 1580, 1449, 1416, 1342, 1285,
1218, 1158, 1113; 1H NMR (DMSO‑d6, 300 MHz) δ
11.99 (s, 1H, −OH), 7.82(dd, J = 8.83 Hz, J = 5.57 Hz,
2H, Ar − H) 7.69 (d, J = 15.70 Hz, 1H, C C H), 7.66
(d, J = 15.90 Hz, 1H, C C H), 7.29 (dd, J = 8.83 Hz,
J = 8.82 Hz, 2H, Ar H), 3.70 (s, 3H, OCH3), 3.61 (s,
3H, OCH3), 2.11 (s, 3H, CH3), 2.06 (s, 3H, CH3);
13C NMR (DMSO‑d6, 150 MHz) δ 193.7 (1C), 163.4 (d,
J = 249.09 Hz, 1C), 162.1 (1C), 158.3 (1C), 157.4 (1C),
142.3 (1C), 131.2 (d, J = 3.06 Hz, 1C), 130.9 (d,
J = 8.67 Hz, 2C), 126.7 (1C), 116.1 (d, J = 21.81 Hz, 2C),
115.4 (1C), 114.7 (1C), 113.5 (1C), 62.0 (1C), 59.9 (1C),
8.8 (1C), 8.7 (1C).
12.14 (s, 1H,
OH), 7.69 (t, J = 18.42 Hz, 2H,
C C H), 7.66 (d, J = 8.19 Hz, 2H, Ar H), 7.33 (d,
J = 8.19 Hz, 2H, Ar H), 3.70 (s, 3H, OCH3), 3.61 (s,
3H, OCH3), 2.93 (septet, J = 6.90 Hz, 1H, CH), 2.11
(s, 3H, CH3), 2.06 (s, 3H, CH3), 1.23 (s, 3H, CH3),
1.21 (s, 3H, CH3); 13C NMR (DMSO‑d6, 150 MHz) δ
193.7 (1C), 162.2 (1C), 158.5 (1C), 157.4 (1C), 151.6
(1C), 143.7 (1C), 132.3 (1C), 128.7 (2C), 127.1 (2C),
126.5 (1C), 125.8 (1C), 114.6 (1C), 113.3 (1C), 61.9 (1C),
59.9 (1C), 33.4 (1C), 23.6 (2C), 8.8 (1C), 8.7 (1C).
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-
3-phenyl-2-propen-1-one (2b).
3 (0.500 g, 2.23 mmol) and benzaldehyde (0.273 mL,
2.68 mmol) in MeOH (20 mL), KOH (0.375 g, 6.68 mmol)
in MeOH (10 mL) was added. The crude product was
To
a
solution of
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-
3-(4-methoxyphenyl)-2-propen-1-one (2e). To a solution
of 3 (0.500 g, 2.23 mmol) and 4-methoxybenzaldehyde
(0.324 mL, 2.68 mmol) in MeOH (20 mL), KOH (0.375 g,
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BULLETIN OF THE
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6.68 mmol) in MeOH (10 mL) was added. The crude prod-
uct was purified via column chromatography to afford 2e
(0.694 g, 2.03 mmol, 91.0%) as a pale orange solid: mp
86–88ꢀC; TLC Rf = 0.68 (n-hexane:acetone = 3:2); IR νmax
(cm−1) 3430, 2936, 1628, 1605, 1556, 1510, 1421, 1348,
(s, 3H, OCH3), 3.61 (s, 3H, OCH3), 2.10 (s, 3H,
CH3), 2.06 (s, 3H, CH3); 13C NMR (DMSO‑d6,
150 MHz) δ 193.5 (1C), 161.9 (1C), 160.3 (1C), 158.6
(1C), 157.4 (1C), 144.6 (1C), 130.8 (2C), 125.6 (1C),
123.0 (1C), 116.0 (2C), 115.3 (1C), 114.6 (1C), 113.2
(1C), 61.9 (1C), 59.9 (1C), 8.8 (1C), 8.7 (1C).
1
1256, 1172, 1141, 1110; H NMR (DMSO‑d6, 300 MHz)
δ 12.19 (s, 1H, OH), 7.71 (d, J = 8.78 Hz, 2H, Ar H),
7.70 (d,
J
=
15.63 Hz, 1H,
C C H), 7.60 (d,
Results and Discussion
J = 15.63 Hz, 1H, C C H), 7.02 (d, J = 8.78 Hz, 2H,
Ar H), 3.82 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 3.61
(s, 3H, OCH3), 2.11 (s, 3H, CH3), 2.06 (s, 3H, CH3);
13C NMR (DMSO‑d6, 150 MHz) δ 193.6 (1C), 162.0 (1C),
161.5 (1C), 158.5 (1C), 157.3 (1C), 143.9 (1C), 130.5
(2C), 127.8 (1C), 127.1 (1C), 124.2 (1C), 114.6 (2C), 114.
6 (1C), 113.3 (1C), 61.9 (1C), 59.9 (1C), 55.4 (1C), 8.8
(1C), 8.7 (1C).
We proposed that the chalcone skeleton of MDMC could be
con-structed via the Claisen–Schmidt condensation of di-O-
methyl-dimethylphloroacetophenone
(3)
with
the
corresponding benzaldehyde (Figure 2). The key intermedi-
ate 3, i.e., the B-ring moiety in which two methyl groups are
alternatively attached between three hydroxy or methoxy
groups, could be obtained by the double O-methylation and
single C-acetylation of dimethylphloroglucinol (4). Interme-
diate 4 could be prepared from commercially available
phloroglucinol.
To develop a more straightforward synthetic route
toward the key intermediate 3 and its substitute, a variety
of synthetic routes starting from phloroacetophenone were
initially investigated. However, all attempts to simulta-
1-(20-Hydroxy-40,60-dimethoxy-30,50-dimethylphenyl)-
3-(4-(methoxymethoxy)phenyl)-2-propen-1-one (2f). To
a
solution
of
3
(0.500 g,
2.23 mmol)
and
4-methoxymethoxybenzaldehyde (0.445 g, 2.68 mmol) in
MeOH (20 mL), KOH (0.375 g, 6.68 mmol) in MeOH
(10 mL) was added. The crude product was purified via
column chromatography to afford 2 f (0.771 g, 2.07 mmol,
92.8%) as a pale orange solid: mp 77–79ꢀC; TLC Rf = 0.69
(n-hexane:acetone = 3:2); IR νmax (cm−1) 3430, 2959,
neously
introduce
two
C-methyl
groups
into
1
phloroacetophenone without affecting the three hydroxyl
groups yielded poor results, as in previous reports.42,43 The
attempted introduction of two C-methyl groups between the
three hydroxyl groups of phloroglucinol to generate 4 were
also unsuccessful primarily due to the competitive O-
methylation of hydroxyl groups. Thus, two methyl groups
had to be introduced to phloroglucinol through a relatively
bypassing synthetic route.41 As shown in Scheme 1, the
Vilsmeier–Haack reaction of phloroglucinol using DMF
and POCl3 produced 2,4-diformylphloroglucinol (5) in an
excellent yield. Product 5 was obtained as a yellow powder
after a simple precipitation with water, and this product
was sufficiently pure to be used in the subsequent step
without any further purification.
1630, 1604, 1560, 1509, 1421, 1346, 1241, 1142, 1110; H
NMR (DMSO‑d6, 300 MHz) δ 12.17 (s, 1H, OH), 7.71
(d, J = 8.76 Hz, 2H, Ar H), 7.63 (t, J = 15.77 Hz, 2H,
C C H), 7.09 (d, J = 8.76 Hz, 2H, Ar H), 5.26 (s, 2H,
CH2 O ), 3.69 (s, 3H, OCH3), 3.61 (s, 3H, OCH3),
3.38 (s, 3H, OCH3), 2.11 (s, 3H, CH3), 2.06 (s, 3H,
CH3); 13C NMR (DMSO‑d6, 150 MHz) δ 193.6 (1C),
162.0 (1C), 158.9 (1C), 158.5 (1C), 157.4 (1C), 143.6
(1C), 130.4 (2C), 128.1 (1C), 127.7 (1C), 124.7 (1C),
116.5 (2C), 115.3 (1C), 114.6 (1C), 113.3 (1C), 93.7 (1C),
61.9 (1C), 59.9 (1C), 55.7 (1C), 8.8 (1C), 8.7 (1C).
Synthesis
of
1-(20-hydroxy-40,60-dimethoxy-30,50-
dimethylphenyl)-3-(4-hydroxyphenyl)-2-propen-1-one
(2g). To a solution of 2f (1.00 g, 2.69 mmol) in MeOH
(300 mL), p-toluenesulfonic acid monohydrate (0.562 g,
2.95 mmol) was added, and the resulting solution stirred
for 36 h at 25ꢀC. Thereafter, the resulting mixture was
diluted with EtOAc (150 mL), washed with water
(3 × 200 mL) and saturated NaCl aqueous solution
(200 mL), and then dried over anhydrous MgSO4. The
organic solvent was evaporated under reduced pressure to
afford the crude product, which was subsequently purified
via column chromatography (n-hexane:acetone = 30:1) to
afford 2g (0.836 g, 2.55 mmol, 94.8%) as a pale orange
solid: mp 138–140ꢀC; TLC Rf = 0.58 (n-hexane:ace-
tone = 3:2); IR νmax (cm−1) 3367, 2962, 1627, 1606, 1551,
1512, 1439, 1348, 1261, 1141, 1108, 1022; 1H NMR
(DMSO‑d6, 300 MHz) δ 12.31 (s, 1H, OH), 10.14 (s,
1H, OH), 7.68 (d, J = 15.49 Hz, 1H, C C H),
7.59 (d, J = 8.58 Hz, 1H, Ar − H), 7.56 (d, J = 15.49 Hz,
2H, C C H), 6.83 (d, J = 8.58 Hz, 2H, Ar H), 3.69
Although typical metal hydride reagents, such as NaBH4,
LiAlH4, and NaBH3CN, were not successful in reducing
both formyl groups of 5, a Clemmensen reduction using
Figure 2. Retrosynthetic analysis for preparation of MDMC
derivatives.
Bull. Korean Chem. Soc. 2020
© 2020 Korean Chemical Society and Wiley-VCH GmbH
www.bkcs.wiley-vch.de
4

BULLETIN OF THE
Article Total Syntheses of 4’,6’-Dimethoxy-2’-Hydroxy-3’,5’-Dimethylchalcone Derivatives KOREAN CHEMICAL SOCIETY
Scheme 2. Preparation of 2g from 2f.
Table 1. Optimization for the deprotection of 2f to prepare 2g.a
Entry
Acid (equiv.)
Temp. (ꢀC)
Time
Yield (%)[b]
1
2
3
4
5
6
7
8
9
36% HCl (4.9)
36% HCl (4.9)
36% HCl (4.9)
1% HCl (1.0)
1% HCl (1.0)
p-TsOH (2.0)
p-TsOH (2.0)
p-TsOH (2.0)
p-TsOH (1.1)
reflux
50
25
50
25
reflux
50
25
20 min
2 h
3 h
20 h
20 h
20 h
20 h
36 h
36 h
50.8
51.2
52.6
53.4
55.9
78.6
80.4
92.6
94.8
25
Scheme 1. Synthetic route toward the MDMC derivatives (2).
a All reactions were performed using 2f (1.00 g) in MeOH (300 mL).
[b] Isolated yields based on 2f.
zinc amalgam efficiently reduced these moieties to give
2,4-dimethylphloroglucinol (4) in a good yield.
Reactions carried out using an excess of aqueous HCl did
not generate good results, regardless of the reaction tempera-
ture employed (Table 1, entries 1–3). Treatment with an exact
equivalent of HCl was also not sufficient (entries 4–5). On
the other hand, p-toluenesulfonic acid (p-TsOH) significantly
reduced the degree of side reactions occurring to increase the
reaction efficiency, in addition to giving a higher yield at
lower temperatures (entries 6–8). The usage of a slight excess
of p-TsOH resulted in the best reaction efficiency (entry 9).
Overall, the optimized reaction conditions involved the reac-
tion of 1.1 equiv. of p-TsOH in MeOH for 36 h at 25ꢀC, to
give 2g in a 94.8% isolated yield.
Attempts to directly introduce two O-methyl groups and
one acetyl group (independent of the order) at the desired
positions of 4 to construct 3 were not successful. This was
attributed to the fact that the regioselective bis-O-
methylation of only two hydroxyl groups was challenging.
In addition, the selective C-acetylation gave poor results in
the presence of a phenolic hydroxyl group. Therefore, an
alternative pathway based on trimethoxyxylene 6, an inter-
mediate bearing no hydroxyl groups and prepared by the
O-methylation of all hydroxyl groups present in 4, was
investigated. The hydroxyl groups of 4 were, therefore,
methylated by reaction with dimethylsulfate (DMS) and
K2CO3 in acetone to generate 6 in a good yield. The
Friedel-Crafts-type acetylation of 6 using acetic anhydride
in the presence of BF3ꢁEt2O not only successfully intro-
duced a single C-acetyl group to the phenyl carbon atom
but also simultaneously removed one ortho-O-methyl group
to directly generate 3.41
Construction of the chalcone skeleton of the desired
MDMC derivatives (2) proceeded well via a Claisen–Schmidt
condensation of 3 with the appropriate benzaldehyde. Follow-
ing brief optimization studies, it was found that the use of
three equivalents of KOH in MeOH was favored. The opti-
mized reaction conditions generated the corresponding com-
pounds 2a–2f in good isolated yields ranging from 89.7 to
94.8%. It was found that additional electrophilic aldehydes,
and in particular 4-fluorobenzaldehyde, reacted faster than
less electrophilic aldehydes.
Conclusion
In summary, we accomplished the total syntheses of
seven 40,60-dimethoxy-20-hydroxy-30,50-dimethylchalcone
(MDMC) derivatives (2). To the best of our knowledge, a
general method for the syntheses of these compounds has
not been reported thus far. The key intermediate 3, which
contained the B-ring moiety of the skeleton, was prepared
via four efficient reaction steps from commercially avail-
able phloroglucinol in a 50.1% overall isolated yield. This
synthetic method allowed the construction of various deriv-
atives 2 in 44.9–47.5% overall yields from phloroglucinol.
Moreover, the synthetic strategy involving construction of
the chalcone skeleton via a Claisen–Schmidt condensation
of the B-ring moiety (3) with various benzaldehydes will
be expected to facilitate pharmacological studies into DMC
derivatives by allowing their rapid and large-scale produc-
tion. The anti-diabetic effects of these compounds are cur-
rently under investigation and the results will be reported in
due course.
The efficiency of the acid-catalyzed cleavage of the MOM
group of 2f to prepare 2g (Scheme 2) was found to be
dependent on the reaction conditions. In particular, cleavage
of the O-methyl groups and a retro-aldol condensation
lowered the yield of 2g.
Bull. Korean Chem. Soc. 2020
© 2020 Korean Chemical Society and Wiley-VCH GmbH
www.bkcs.wiley-vch.de
5

BULLETIN OF THE
Article Total Syntheses of 4’,6’-Dimethoxy-2’-Hydroxy-3’,5’-Dimethylchalcone Derivatives KOREAN CHEMICAL SOCIETY
22. Y. Hadisaputri, N. Cahyana, M. Muchtaridi, R. Lesmana, T.
Rusdiana, A. Y. Chaerunisa, I. Sufiawati, T. Rostinawati, A.
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Acknowledgments. This research was supported by the
Chung-Ang University Graduate Research Scholarship
in 2017.
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6