Synthesis and characterization of novel unnatural bichalcones

Article abstract of DOI:10.1007/s12272-010-1205-2

Five bichalcones (5-1 ～ 5-4, 9) were prepared by the reaction of biphenyl-4,4′-dicarbaldehyde (4) and 4,4′-dioxybenzaldehyde (8) with the respective acetophenone analogs via Claisen-Schmidt condensation and were then fully identified by 1H-NMR, ¹³C-NMR and mass analyses.

Full text of DOI:10.1007/s12272-010-1205-2

Arch Pharm Res Vol 33, No 12, 1919-1926, 2010
DOI 10.1007/s12272-010-1205-2
Synthesis and Characterization of Novel Unnatural Bichalcones
Santosh K. Gurung, Soo Bae Kim, and Haeil Park
College of Pharmacy, Division of Medicinal Chemistry, Kangwon National University, Chuncheon 200-701, Korea
(Received May 25, 2010/Revised September 2, 2010/Accepted October 5, 2010)
Five bichalcones (5-1
~ 5-4, 9) were prepared by the reaction of biphenyl-4,4'-dicarbaldehyde
(4) and 4,4'-dioxybenzaldehyde (8) with the respective acetophenone analogs via Claisen-
Schmidt condensation and were then fully identified by H-NMR, 13C-NMR and mass analy-
ses.
1
Key words: Bichalcones, Chalcone dimers, Claisen-Schmidt condensation, Suzuki-Miyaura
reaction, Stille reaction, Ullmann diaryl ether synthesis
been reported to show activities on melanoma and
colon cancer cell lines (Mdee et al., 2003). Therefore,
INTRODUCTION
Plant flavonoids are previously demonstrated to efficient synthetic pathways for diverse bichalcones are
possess anti-inflammatory activity in vitro and in vivo required.
(Amellal et al., 1985; Sun et al., 1997; Lin et al., 2001).
The total syntheses of C-C and C-O-C bichalcone
Biflavonoids, one of the subclasses of flavonoids, are were initiated by retrosynthetic analysis as shown in
flavonoid dimers having a C-C or C-O-C linkage be- Scheme 1. On doing retrosynthetic analyses of design-
tween monomers. Several biflavonoids such as ament- ed C-C and C-O-C bichalcones, the C-C bichalcones
oflavone, ochnaflavone and ginkgetin (Fig. 1) were for could be synthesized by dimerization of chalcone units
the first time found to be inhibitors of group II se- where direct C-C coupling of two monomeric chalcone
cretory phospholipase A2 (sPLA2 IIA) (Sawada et al., units occurs under the Suzuki-Miyaura (Miyaura and
1999). Morelloflavone (Fig. 1), a flavone-flavanone Suzuki, 1995) and Stille coupling condition (Stille,
dimer, was also revealed as a sPLA2 inhibitor (Shinohara 1995). Also C-O-C bichalcones could be synthesized by
et al., 1999). Moreover, it was found that certain bifla- dimerization of chalcone units where direct C-O-C
vonoids such as ginkgetin exerted the inhibitory acti- coupling of two monomeric chalcone units occurs under
vity against COX-2-mediated PGE2 production and Ullmann type diaryl ether synthesis (Sawyer, 2000).
iNOS-mediated NO production from macrophages
Our initial attempts at syntheses employed Suzuki-
mainly by an inhibition of COX-2 and iNOS expres- Miyaura and Stille coupling were not successful
sion (Murakami et al., 1998, 1999). Recently, some C- though the pathways were more straightforward and
C biflavonoids were prepared and they were found to versatile procedures for synthesis of diverse symme-
be PLA2 inhibitors and inhibitors of PGE2 production trical and unsymmetrical C-C bichalcones. Also reac-
(Kim et al., 1999; Chen et al., 2006). Bichalcones are tion conditions of Ullmann type diaryl ether synthesis
very interesting targets for synthesis since some were tried for synthesis of C-O-C bichalcones but no
chalcones were previously found to strongly inhibit good result was observed (Scheme 1). Therefore, other
iNOS-mediated NO production from macrophages synthetic procedures for C-C and C-O-C bichalcones
(Kim et al., 2007) and several natural bichalcones (Fig. were explored. Herein, we report procedures for syn-
1) isolated from the root bark of Rhus pyroids, have theses of novel unnatural C-C and C-O-C bichalcones
via Claisen-Schmidt condensation of biphenyl-4,4'-
dicarbaldehyde (
4) and 4,4'-oxydibenzaldehyde (8) with
the respective acetophenones.
Correspondence to: Haeil Park, College of Pharmacy, Division of
Medicinal Chemistry, Kangwon National University, Chun-
cheon 200-701, Korea
Tel: 82-33-250-6920, Fax: 82-33-255-7865
E-mail: haeilp@kangwon.ac.kr
1919

1920
S. K. Gurung et al.
Fig. 1. Chemical structures of naturally occurring biflavonoids and bichalcones
Scheme 1. Retrosynthetic analyses for C-C and C-O-C bichalcones
trometer, fully decoupled and chemical shifts are re-
ported in parts per million (ppm) downfield relative to
MATERIALS AND METHODS
All chemicals were obtained from commercial sup- tetramethylsilane as an internal standard. Melting
pliers, and used without further purification. All solv- points were recorded on a Fisher-Johns microscopic
ents used for reaction were freshly distilled from pro- scale melting point apparatus. EI mass spectra were
per dehydrating agent under nitrogen gas. All solvents recorded on a Autospec M363. Analytical thin-layer
used for chromatography were purchased and directly chromatography (TLC) was performed using commer-
1
applied without further purification. H-NMR spectra cial glass plate with silica gel 60F254 purchased from
were recorded on a Varian Gemini 2000 (200 MHz) and Merck. Chromatographic purification was carried out
a Bruker DPX 400 (400 MHz) spectrometers. Chemical by flash chromatography using Kieselgel 60 (230~400
shifts are reported in parts per million (ppm) down- mesh, Merck).
field relative to tetramethylsilane as an internal
standard. Peak splitting patterns are abbreviated as
m (multiplet), s (singlet), bs (broad singlet), d (doublet),
bd (broad doublet), t (triplet), dd (doublet of doublets)
and ddd (doublet of double doublet). 13C-NMR spectra
Reaction conditions for synthesis of C-C bi-
chalcones intermediates (2, 3, & 4)
Diethyl biphenyl-4,4'-dicarboxylate (2)
Reactions of 4-bromobenzoic acid in ethanol with
were recorded on a Bruker DPX 400 (100 MHz) spec- concentrated sulfuric acid provided ethyl 4-bromo-

Synthesis and Characterization of Novel Unnatural Bichalcones
1921
1
benzoate (
1
) in 95% yield after purification. A flask crystal in 54% yield; m.p. 188-191oC; H-NMR (200
charged with ethyl 4-bromobenzoate (1.3 mmol, 0.21 MHz, CDCl3):
mL), bis(pinacolato)diboron (0.36 gm, 1.44 mmol), an- H3, H3', H5, H5'), 7.37~7.44 (t, 4H,
hydrous KOAc (0.51 gm, 5.2 mmol) and PdCl2(dppf) H2, H2', H6, H6'), 4.61~4.67 (t, 4H,
δ
7.54~7.62 (t, 4H, = 8.0 Hz, 7.6 Hz,
J
J
= 7.8 Hz, 7.2 Hz,
= 5.6 Hz, 7.6 Hz,
J
(0.05 gm, 0.065 mmol) were flushed with nitrogen.
DMF (6.5 mL) was added to the reaction mixture and
the reaction was stirred at 80oC for 2 h. After cooling
the solution to room temperature, ethyl 4-bromoben-
2 × CH2).
Biphenyl-4,4'-dicarbaldehyde (4)
Biphenyl-4,4'-diyldimethanol (1.5 gm, 7.0 mmol) was
zoate (0.6 gm, 2.6 mmol), PdCl2(dppf) (0.053 gm, 0.065 dissolved in 30 mL of anhydrous methylene chloride.
mmol) and potassium phosphate (0.82 gm, 3.9 mmol) To a two necked round bottom flask containing pyri-
were added and the reaction mixture was stirred at dinium chlorochromate (PCC) (4.52 gm, 21.0 mmol)
100oC under nitrogen overnight. The solution was and 4 Å MS (0.5 gm) was added 30 mL of fresh dry
cooled to room temperature and filtered through methylene chloride. The alcohol suspension was drop-
filtering agent. The filtrate was extracted with ethyl ped slowly through addition funnel to the PCC solu-
acetate and the excess DMF was destroyed with 3% tion with gentle stirring using the magnetic stir bar at
aqueous HCl solution. The organic layer was washed room temperature under nitrogen. Once the addition
with brine, dried over anhydrous MgSO4 and filtered was complete, the reaction mixture was refluxed for 2
with a glass filter. The filtrate was concentrated under h. After the completion of the reaction, the reaction
reduced pressure using rotary evaporator. The crude mixture was cooled to room temperature. The solvent
residue was purified by column chromatography using layer was decanted from the tarry black residue, and
hexane:ethyl acetate (20:1) as a mobile phase. The the residue was rinsed twice with about 20 mL of
product was further purified by recrystallisation in methylene chloride. The combined methylene chloride
hot MeOH to afford the target compound as white solution was evaporated on a rotary evaporator. The
needle crystal in 62% yield; m.p. 108-111oC; 1H-NMR residue was diluted with 50 mL of diethyl ether and
(200 MHz, CDCl3):
H3', H5, H5'), 7.66~7.70 (d, 4H,
H6, H6'), 4.35~4.42 (q, 4H, = 6.6 Hz, 7.00 Hz, 2
CH2), 1.38~1.44 (t, 6H, = 6.6 Hz, 2 CH3 ).
δ
8.11~8.15 (d, 4H,
J = 7.2 Hz, H3, filtered through cotton plug to remove the insoluble
J
= 7.8 Hz, H2, H2', chromium salts. The ether layer was washed with 20
J
×
mL of aqueous 1 M NaOH solution, followed by 20 mL
of brine solution, dried over anhydrous MgSO4 and fil-
tered with a glass filter. The filtrate was concentrated
in reduced pressure and the crude residue was recry-
J
×
Biphenyl-4,4'-diyldimethanol (3)
To an ice-cold solution of diethyl biphenyl-4,4'-dicar- stallised in hot MeOH to afford the target compound
1
boxylate (0.30 gm, 1.0 mmol) in anhydrous THF (3.3 as white solid in 65% yield; m.p. 188-191oC; H-NMR
mL) was added LiAlH4 (freshly ground powder form (200 MHz, CDCl3):
from lump, 0.11 gm, 3.0 mmol) was added slowly under Hz, H3, H3', H5, H5'), 7.36~7.44 (t, 4H,
nitrogen with slow stirring so that without forming Hz, H2, H2', H6, H6'), 4.61~4.67 (t, 4H,
δ
7.54~7.62 (t, 4H,
J
J
J
= 8.0 Hz, 7.6
= 7.8 Hz, 7.2
= 5.6 Hz, 7.6
any crust layer at the wall, bottom and upper layer of Hz, 2
flask. The mixture was stirred for 30 min at ice-cold
× CH2).
bath and continued to reflux for overnight. The reac-
tion mixture was cooled to room temperature and the
excess of LiAlH4 was destroyed by slow addition of
Reaction conditions for C-C bichalcones (5-1, 5-
2, 5-3 and 5-4) by Claisen-Schmidt condensation
To a suspension of the respective acetophenone
aqueous saturated solution of Na2SO4·10H2O at ice- analogs (1.9 mmol) and biphenyl-4,4'-dicarbaldehyde
cold bath. The solution was refluxed for 30 min, brought
(4, 0.2 gm, 0.95 mmol) in 2 mL of anhydrous methyl
to room temperature, filtered through filtering agent alcohol was added finely divided KOH (0.16 g, 2.85
and washed with THF (10 mL). The THF from filtrate mmol). The resultant mixture was stirred for 2 day at
was evaporated under reduced pressure by rotary evap- room temperature. An excess volume of aqueous HCl
orator and the residue was extracted with ethyl acetate. (3%) solution was added while stirring. The precipit-
The organic layer was washed with brine, dried over ate was filtered and the crude solid residue was
with anhydrous MgSO4 and filtered by a glass filter. washed with MeOH several times using vortex till the
The filtrate was concentrated in reduced pressure. single spot was observed by TLC.
The crude residue was purified by column chromatog-
raphy using hexane:acetone (5:2) as a mobile phase.
The product was further purified by recrystallisation 2-ene) (5-1)
in hot MeOH to afford the target compound as white
Pale yellow solid, 62%; m.p. 228-231oC; 1H-NMR (400
(2E,2'E)-3,3'-(Biphenyl-4,4'-diyl)-bis(1-phenylprop-

1922
S. K. Gurung et al.
MHz, CDCl3):
δ
8.04~8.06 (d, 4H,
= 15.7 Hz, H
= 8.3 Hz, H3', H3''), 7.69~7.71 (d, 4'OMe, 4''OMe), 3.85 (s, 6H, 6'OMe, 6''OMe); 13C-NMR
= 8.4 Hz, H5', H5''), 7.57~7.61 (m, 8H, H , H (100 MHz, CDCl3): 192.88 (2 C=O), 168.87 (C-4', C-
H4, H4''', H3, H3''', H5, H5'''), 7.51~7.55 (t, 4H, = 7.7 4''), 166.70 (C-6', C-6''), 162.90 (C-2', C-2''), 142.15 (C-
Hz, 7.2 Hz, H2, H2''', H6, H6'''); 13C-NMR (100 MHz,
, C- '), 142.09 (C-4, C-4'''), 135.49 (C-1, C-1'''), 129.39
CDCl3): 190.861 (2 C=O), 144.54 (C- , C- '), 142.51 (C-3, C-3''', C-5, C-5'''), 128.11 (C- , C- '), 127.82 (C-1, C-
J
= 8.5 Hz, H2', H2'', H5, H5'''), 6.10~6.13 (d, 2H,
J
= 2.2 Hz, H5', H5''),
H6', H6''), 7.84~7.88 (d, 2H,
7.74~7.76 (d, 2H,
2H,
J
α
, H '), 5.98~5.99 (d, 2H,
α
J = 2.1 Hz, H3', H3''), 3.95 (s, 6H,
J
J
β
β'
δ
×
J
α
α
δ
×
α
α
β
β
(C-4, C-4'''), 138.6 (C-1', C-1''), 134.87 (C-4', C-4''), 133.29 1'''), 106.78 (C-1', C-1''), 94.21 (C-3', C-3''), 91.74 (C-5', C-
(C-1, C-1'''), 129.51 (C-3', C-3'', C-5', C-5''), 129.09 (C-2', 5''), 56.32 (4'OMe, 4''OMe), 56.05 (6'OMe, 6''OMe) m/z
C-2'', C-6', C-6''), 128.94 (C-3, C-3''', C-5, C-5'''), 127.94 566 (M+, 56), 414 (34), 368 (27), 207 (100), 181 (78), 129
(C-2, C-2''', C-6, C-6'''), 122.63 (C-
11), 414 (100), 312 (9), 207 (43), 178 (16), 145 (16).
β, C-β
'); m/z 416 (M+, (38).
Reaction conditions for synthesis of C-O-C bi-
chalcone intermediates (6, 7 & 8)
(2
phenyl)prop-2-ene) (5-2)
Yellow solid, 50%; m.p. 257-259oC; H-NMR (400
MHz, CDCl3): 12.83 (s, 2H, OH), 7.96~8.00 (m, 4H, solved in ethyl alcohol (15 mL). To the solution, con-
, H ', H6', H6''), 7.71~7.80 (m, 8H, H , H ' H4, centrated sulfuric acid (1 mL) was added and refluxed
H4''', H3, H3''', H5, H5'''), 7.51~7.55 (t, 2H, = 1.2 Hz, for 5 h. After the completion of reaction, the reaction
8.4 Hz, H2, H2'''), 7.04~7.07 (d, 2H, = 8.5 Hz, H3', mixture was cooled to room temperature. The saturat-
H3''), 6.96~7.00 (t, 2H, = 0.9 Hz, 8.3 Hz, H6, H6'''); ed solution of aqueous NaHCO3 was added till pH 7.
13C-NMR (100 MHz, CDCl3):
193.99 (2 C=O), 164.05 The precipitated out solid was filtered and washed
(C-2', C-2''), 145.12 (C- , C- '), 142.78 (C-4, C-4'''), with excess water. The white solid was air dried and
E,2'E)-3,3'-(Biphenyl-4,4'-diyl)-bis(1-(2-hydroxy-
Diethyl 4,4
'-dioxybenzoate (6)
1
4-Hydroxybenzoic acid (2.0 gm, 14.5 mmol) was dis-
δ
Hα
α
β
J
β
J
J
δ
α
×
α
136.92 (C-4', C-4''), 134.66 (C-1, C-1'''), 130.05 (C-6', C- used for the next reaction without further purifica-
6''), 129.75 (C-3, C-3''', C-5, C-5'''), 128.04 (C-2, C-2''', tion. To a flask containing ethyl 4-hydroxybenzoate
C-6, C-6'''), 120.73 (C-5', C-5''), 120.44 (C-1', C-1''), (0.2 gm, 1.2 mmol), copper (I) iodide (0.012 gm, 0.06
119.31 (C-
74), 191 (28), 178 (40), 147 (87), 121 (100), 92 (28).
β, C-β -
'), 119.12 (C-3', C-3''); m/z 446 (M+, mmol), cesium carbonate (0.08 gm, 0.024 mmol), N,N
dimethylglycine (0.002 gm, 0.024 mmol) was added
freshly dried 1,4-dioxane (2.4 mL) through syringe. To
the reaction mixture, ethyl-4-bromobenzoate (0.2 mL,
1.2 mmol) was added and degassed by nitrogen for 10
(2
E,2'E)-3,3'-(Biphenyl-4,4'-diyl)-bis(1-(2-hydroxy-
6-methoxyphenyl)prop-2-ene) (5-3)
Yellow solid, 60%; m.p. 236-239oC; H-NMR (400 min. The reaction mixture was refluxed for 1 day. The
1
MHz, CDCl3):
= 15.6 Hz, H
, H '), 7.68~7.74 (dd, 8H,
H2''', H6, H6''', H3, H3''', H5, H5'''), 7.36~7.41 (t, 2H,
= 8.3 Hz, H4', H4''), 6.63~6.65 (d, 2H, = 8.4 Hz, H5', anhydrous MgSO4 and filtered with a glass filter. The
= 8.3 Hz, H3', H3''); 13C- filtrate was concentrated in reduced pressure. The
194.74 (2 C=O), 165.30 (C- crude residue was purified by column chromatography
, C- '), 142.34 using hexane:ethyl acetate (10:1) as a mobile phase to
δ
13.14 (s, 2H, OH), 7.91~7.95 (d, 2H,
, H '), 7.84~7.88 (d, 2H, = 15.6 Hz, evaporated under reduced pressure to remove 1,4-
= 8.5 Hz, 4.4 Hz, H2, dioxane. The residue was extracted with ethyl acetate.
The organic layer was washed with brine, dried over
J
reaction mixture was cooled to room temperature and
α
α
J
Hβ
β
J
J
J
H5''), 6.45~6.47 (d, 2H,
NMR (100 MHz, CDCl3):
6', C-6''), 161.39 (C-2', C-2''), 142.66 (C-
J
δ
×
α
α
1
(C-4, C-4'''), 136.42 (C-4', C-4''), 135.30 (C-1, C-1'''), afford product as colorless oil in 35% yield. H-NMR
129.51 (C-3, C-3''', C-5, C-5'''), 128.19 (C- , C- '), (200 MHz, CDCl3): 7.98~8.02 (d, 4H, = 7.8 Hz, H3,
127.88 (C-2, C-2''', C-6, C-6'''), 112.43 (C-1', C-1''), H3', H5, H5'), 6.98~7.02 (d, 4H, = 7.4 Hz, H2, H2',
= 6.5 Hz, 7.00 Hz, 2
= 6.6 Hz, 7.1 Hz, 2 CH3).
β
β
δ
J
J
111.43 (C-3', C-3''), 101.98 (C-5', C-5''), 56.42 (2X H6, H6'), 4.35~4.41 (q, 4H,
J
×
OMe); m/z 506 (M+,100), 505 (84), 355 (48), 206 (56), CH2), 1.32~1.40 (t, 6H,
J
×
193 (43), 177 (98), 151 (92).
4,4
To an ice-cold solution of diethyl 4,4'-dioxybenzoate
, 0.17gm , 0.55 mmol) in anhydrous THF (3.0 mL) was
Yellow solid, 57%; m.p. 261-264oC; H-NMR (400 added LiAlH4 (freshly ground powder form from lump,
'-Oxy-bis(4,1-phenylene) dimethanol (7)
(2E,2'E)-3,3'-(Biphenyl-4,4'-diyl)-bis(1-(2-hydroxy-
4,6-dimethoxyphenyl)prop-2-ene) (5-4)
(6
1
MHz, CDCl3):
δ
14.32 (s, 2H, OH), 7.94~7.98 (d, 2H,
J
0.062 gm, 1.65 mmol) was added portionwise under
nitrogen with slow stirring so that without forming
= 15.5 Hz, H , H
β
β
'), 7.81~7.85 (d, 2H, = 15.5 Hz, Hα,
J
Hα'), 7.67~7.72 (m, 8H, H2, H2''', H3, H3''', H6, H6''', any crust layer in the wall, bottom and upper layer

Synthesis and Characterization of Novel Unnatural Bichalcones
1923
flask. The mixture was stirred for 30 min at ice-cold mmol) was dissolved in 25 mL of anhydrous methyl-
bath and continued to reflux for overnight. After the ene chloride. To a two necked round bottom flask con-
reaction mixture was cooled to room temperature, taining pyridinium chlorochromate (PCC) (4.21 gm,
excess LiAlH4 was destroyed by slowly adding satura- 19.5 mmol) and 4 Å MS (0.5 gm) was added fresh dry
ted aqueous of Na2SO4.10H2O in ice-cold bath. The methylene chloride (25 mL). The alcohol suspension
reaction mixture was refluxed for 30 min, cooled to was dropped slowly through addition funnel to the
room temperature and filtered through filtering reag- PCC solution with gentle stirring at room tempera-
ent. Filter cake was washed with THF (10 mL) and ture under nitrogen. Once the addition was complete,
filtrate THF solution was evaporated under reduced the reaction mixture was refluxed for 2 h. After the
pressure and extracted with ethyl acetate. The organic completion of the reaction, the reaction mixture was
layer was washed with brine, dried over anhydrous cooled to room temperature. The solvent layer was
MgSO4 and filtered with a glass filter. The filtrate was decanted from the tarry black residue, and the residue
concentrated in reduced pressure using rotary evap- was rinsed twice with about 20 mL of methylene chlor-
orator. The crude residue was purified by column chro- ide. The combined methylene chloride solution was
matography using hexane:acetone (5:2) as a mobile evaporated on a rotary evaporator. The residue was
phase. The product was further recrystallised in hot diluted with 50 mL of diethyl ether and filtered through
MeOH to afford product as white solid in 50% yield; cotton plug to remove the insoluble chromium salts.
1
m.p. 127-133oC; H-NMR (200 MHz, CDCl3):
7.30 (d, 4H,
δ 7.26~ The ether layer was washed with 20 mL of 1 M NaOH
J = 8.4 Hz, H3, H3', H5, H5'), 6.85~6.89 (d, aqueous solution, followed by 20 mL of brine solution,
4H, = 8.8 Hz, H2, H2', H6, H6'), 4.52 (s, 4H, 2
J
×
CH2).
dried over anhydrous MgSO4 and filtered with a glass
filter. The filtrate was concentrated in reduced pres-
sure using rotary evaporator. The crude residue was
4,4'-Oxydibenzaldehyde (8)
4,4'-Oxybis(4,1-phenylene)dimethanol (7, 1.5 gm, 6.5 recrystallised in hot MeOH to afford the target com-
Scheme 2. Retrosynthetic analysis and synthetic pathway of C-C bichalcones

1924
S. K. Gurung et al.
1
pound as white solid in 65% yield; m.p. 56-58oC; H- 4''OMe), 3.84 (s, 6H, 6'OMe, 6''OMe); 13C-NMR (100
NMR (200 MHz, CDCl3): 9.99 (s, 2H, 2 CHO), 7.91 MHz, CDCl3): 192.43 (2 C=O), 168.43 (C-4', C-4''),
~7.95 (d, 4H, = 8.2 Hz, H3, H3', H5, H5'), 7.16~7.20 166.22 (C-6', C-6''), 162.46 (C-2', C-2''), 158.25 (C-4, C-
(d, 4H, = 8.0 Hz, H2, H2', H6, H6'). 4'''), 141.51 (C- , C- '), 132.00 (C-2, C-2''', C-6, C-6'''),
130.24 (C- , C- '), 126.69 (C-1', C-1''), 119.29 (C-3, C-
δ
×
δ
×
J
J
α
α
β
β
(2E,2'
E)-3,3'-(4,4'-Oxybis(4,1-phenylene))-bis(1-(2-
3''', C-5, C-5'''), 106.30 (C-1, C-1'''), 93.82 (C-3', C-3''),
91.28 (C-5', C-5''), 55.86 (4'OMe, 4''OMe), 55.60 (6'OMe,
hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one) (9)
To a suspension of 2'-hydroxy-4', 6'-dimethoxyaceto- 6''OMe); m/z 582 (M+, 100), 389 (36), 207 (54), 181
phenone (0.21gm, 2.65 mmol) and 4, 4'-oxydibenzalde- (99), 154 (23), 69 (20).
hyde (0.3 gm, 1.32 mmol) in 2 mL of anhydrous methyl
alcohol and 1 mL of anhydrous THF was added finely
divided KOH (0.44 gm, 3.96 mmol). The resultant
mixture was stirred for 2 day at room temperature.
RESULTS AND DISCUSSION
In this study, five C-C and C-O-C bichalcones were
An excess volume of aqueous HCl (3%) solution was prepared via the reaction of biphenyl-4,4'-dicarbalde-
added while stirring. The precipitate was filtered and hyde ( ) and 4,4'-dioxybenzaldehyde ( ) with the re-
4
8
the crude solid residue was washed with MeOH sev- spective acetophenone analogs via Claisen-Schmidt
eral times using vortex till the single spot was observ- condensation (Dao et al., 2004). The general synthetic
ed by TLC. Yellow solid, 41%; m.p. 157-159oC; 1H-NMR strategy employed to synthesize the C-C bichalcone
(400 MHz, CDCl3):
2H, = 15.6 Hz, H
Hz, H , H '), 7.59~7.61 (d, 4H,
H6, H6'''), 7.05~7.07 (d, 4H, = 8.0 Hz, H3, H3''', H5, midt condensation, was prepared from commercially
H5''), 6.10~6.11 (d, 2H, = 2.0 Hz, H3', H3''), 5.96~5.97 available 4-bromobenzoic acid in good yields. Prepara-
(d, 2H, = 1.8 Hz, H5', H5''), 3.91 (s, 6H, 4'OMe, tion of the key intermediate from 4-bromobenzalde-
δ
14.34 (s, 2H, OH), 7.83~7.87 (d, analogs (5-1
, H '), 7.75~7.79 (d, 2H, = 15.6 Schmidt condensation as the key reaction. 4,4'-Dicar-
= 8.5 Hz, H2, H2''', baldehyde ( ), the key intermediate for Claisen-Sch-
, 5-2, 5-3 and 5-4) based on Claisen-
J
β
β
J
α
α
J
4
J
J
J
4
Scheme 3. Retrosynthetic analysis and synthetic pathway of C-O-C bichalcones

Synthesis and Characterization of Novel Unnatural Bichalcones
1925
hyde following the precedent literatures (Moutloali et search Program through the National Research Foun-
al., 2002; Kuhnert et al., 2005) yielded extremely low dation of Korea (NRF) funded by the Ministry of Edu-
yields of the product. Reaction of ethyl 4-bromobenzo- cation, Science and Technology (Grant 2009-0072124:
ate and bis(pinacolato) diboron with catalytic amount Synthesis of Biologically Active Flavonoids Analogues).
of Pd-catalyst provided 4-(4,4,5,5-tetramethyl-[1,3,2] The authors thank to Pharmacal Research Institute
dioxaborolan-2-yl)-benzoic acid ethyl ester in situ and Central Laboratory of Kangwon National Univer-
(Giroux et al., 1997). Suzuki-Miyaura C-C cross coupl- sity for the use of analytical instruments and bioassay
ing reaction of the intermediate and ethyl 4-bromo- facilities.
benzoate produced 4,4'-dicarbaldehyde (
Scheme 1. Novel synthetic C-C bichalcone analogs (5-
5-2 5-3 and 5-4) were synthesized by base-cata-
lyzed condensation of biphenyl-4,4'-dicarbaldehyde (
and the respective acetophenone analogs via Claisen-
Schmidt condensation in 62%, 50%, 60% and 57%
yields, respectively.
4) as shown in
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