Facile method for the large-scale synthesis of 6,7,4′-trihydroxyisoflavanone

Article abstract of DOI:10.1080/00397911.2014.886331

6,7,4′-Trihydroxyisoflavanone, the main source of which is extracted from soybeans, has been found to have diverse significant bioactivities. A large-scale, cost-effective, and facile chemical synthesis of 6,7,4′-trihydroxyisoflavanone is presented herein. Its synthesis is characterized by three steps with an overall yield of 71% and a purity or more than 99.0%. This reaction can be scaled up to multikilogram quantities, providing a solid basis for its further bioactivity studies and drug development. With this same method, 6,7,3′,4′-tetrahydroxyisoflavanone, an analog of 6,7,4′-trihydroxyisoflavanone, also can be largely prepared, indicating this modified synthetic method is potentially available for large-scale synthesis of a broad range of multihydroxyl isoflavanones.

Full text of DOI:10.1080/00397911.2014.886331

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Facile Method for the Large-
Scale Synthesis of 6,7,4′-
Trihydroxyisoflavanone
Jing Liu a , Zhangyou Yang a , Shenglin Luo a , Yuhui Hao a , Jiong Ren
a , Yongping Su a , Weidong Wang b & Rong Li a
a Institute of Combined Injury, State Key Laboratory of Trauma,
Burns, and Combined Injury, Chongqing Engineering Research Center
for Nanomedicine, College of Preventive Medicine , Third Military
Click for updates
Medical University , Chongqing , China
b Department of Radiation Oncology , Sichuan Cancer Hospital ,
Chengdu , China
Accepted author version posted online: 15 Apr 2014.Published
online: 26 Sep 2014.
To cite this article: Jing Liu , Zhangyou Yang , Shenglin Luo , Yuhui Hao , Jiong Ren , Yongping
Su , Weidong Wang & Rong Li (2014) Facile Method for the Large-Scale Synthesis of 6,7,4′-
Trihydroxyisoflavanone, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 44:22, 3296-3303, DOI: 10.1080/00397911.2014.886331
To link to this article: http://dx.doi.org/10.1080/00397911.2014.886331
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Synthetic Communications1, 44: 3296–3303, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.886331
FACILE METHOD FOR THE LARGE-SCALE SYNTHESIS
OF 6,7,4’-TRIHYDROXYISOFLAVANONE
Jing Liu,1 Zhangyou Yang,1 Shenglin Luo,1 Yuhui Hao,1
Jiong Ren,1 Yongping Su,1 Weidong Wang,2 and Rong Li1
1Institute of Combined Injury, State Key Laboratory of Trauma, Burns and
Combined Injury, Chongqing Engineering Research Center for
Nanomedicine, College of Preventive Medicine, Third Military Medical
University, Chongqing, China
2Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu,
China
GRAPHICAL ABSTRACT
Abstract 6,7,40-Trihydroxyisoflavanone, the main source of which is extracted from
soybeans, has been found to have diverse significant bioactivities. A large-scale, cost-
effective, and facile chemical synthesis of 6,7,40-trihydroxyisoflavanone is presented herein.
Its synthesis is characterized by three steps with an overall yield of 71% and a purity or
more than 99.0%. This reaction can be scaled up to multikilogram quantities, providing a
solid basis for its further bioactivity studies and drug development. With this same method,
6,7,30,40-tetrahydroxyisoflavanone, an analog of 6,7,40-trihydroxyisoflavanone, also can be
largely prepared, indicating this modified synthetic method is potentially available for
large-scale synthesis of a broad range of multihydroxyl isoflavanones.
Received August 27, 2013.
Jing Liu and Zhangyou Yang contributed equally to this work.
Address correspondence to Weidong Wang, Sichuan Cancer Hospital, Chengdu 610041, China.
E-mail: wwdwyl@sina.com or Rong Li, College of Preventive Medicine, Third Military Medical
University, 30 Gaotanyan Road, Chongqing 400038, China. E-mail: lrong361@126.com
3296

SYNTHESIS OF 6,7,40-TRIHYDROXYISOFLAVANONE
3297
Keywords Demethylation; deoxybenzoin; Houben–Hoesch reaction; isoflavanone;
large-scale synthesis
INTRODUCTION
Ortho-dihydroxyisoflavone has been found to have a wide range of biological
activities related to its oestrogen-like structure and effect.[1–3] 6,7,40-Trihydroxyisofla-
vanone, an ortho-dihydroxyisoflavone with significant antioxidant, anti-inflamma-
tory, and antitumor properties, is drawing growing scientific interest.[4–6] Recently,
6,7,40-trihydroxyisoflavanone was found to inhibit fat droplet formation[7] and to
inhibit the proliferation of HCT-116 human colon cancer cells by targeting CDK1
and CDK2.[8] However, currently the main source of 6,7,40-trihydroxyisoflavanone
is extracted from soybean. The limited quantity and purity of this compound via
extract from soybean severely restrict further studies on its bioactivities and applica-
tions. This situation has prompted the development of a chemical synthesis for
6,7,40-trihydroxyisoflavanone.
There are a few methods reported for the total synthesis of 6,7,40-trihydroxyiso-
flavanone. The first synthesis was developed by Vasquez-Martinez et al.[9] using
3,4-dihydroxyphenol and p-hydroxy phenylacetonitrile as the starting materials
and proceeds through the Houben–Hoesch reaction, recarburization, and cyclization.
However, this method requires the use of a low reaction temperature (0 ꢀC), solvents
with low boiling points (diethyl ether), and toxic reagents (methanesulfonyl chloride);
therefor the synthesis of the target product is limited to the gram scale and has a poor
total yield. Goto et al. developed a one-pot synthetic method to obtain 6,7,40-
trihydroxyisoflavanone.[10] Although this synthetic method is characterized by a short
route, its total yield is extremely poor (8%) and further purification is required.
Consequently, the disadvantages of these published methods hamper the large-scale
preparation and further biological investigation of 6,7,40-trihydroxyisoflavanone.
Herein, we present a new total synthetic route to prepare 6,7,40-trihydroxyisoflava-
none (Scheme 1). This reaction can be scaled up to kilogram quantities and is
Scheme 1. Synthetic route for 6,7,40-trihydroxyisoflavanone.

3298
J. LIU ET AL.
performed under more facile conditions as compared to the previously reported
methods. With this method, 6,7,30,40-tetrahydroxyisoflavanone, an analog of 6,7,40-
trihydroxyisoflavanone, also can be largely synthesized (Scheme S1 and Figs. S8–S11
in Supporting information), showing the new synthetic method is potentially available
for large-scale synthesis of a broad range of multihydroxyl isoflavanones.
RESULTS AND DISCUSSION
Synthesis of 3,4-Dimethoxyl-4’-hydroxyl-deoxybenzoin (3)
To prepare large quantities of 6,7,40-trihydroxyisoflavanone, deoxybenzoin (3),
the key intermediate, must be obtained with high efficiency. Deoxybenzoins are gen-
erally obtained by the electrophilic substitution of appropriate phenols with benzyl
cyanides (Hoesch reaction) using a ZnCl2=HCl catalyst system.[11,12] The first step in
the reaction mechanism is the formation of a nitrilium chloride that is subsequently
transformed to an imino chloride (5 in Scheme 2). The initial imino chloride is
further hydrolyzed to afford the final product, an aromatic ketone. To improve
the reactivity and selectivity of this reaction, we changed the starting material from
3,4-dihydroxyphenol to 3,4-dimethoxyphenol, because the electrophilicity of the
phenol was greatly enhanced and the regioselectivity at the 6-position in the electro-
philic substitution was reinforced. In addition, diethyl ether, the traditional solvent
used in this reaction, was replaced by 1,4-dioxane, which has better solubility and a
higher boiling point. Moreover, we carefully implemented multifactor experimental
designs to simplify the practical operation (including reactant ratio between
compound 1 and 2, reaction temperature, and time), and we reduced the requirement
for harsh reaction conditions (Table S1, in Supporting Information). Our procedure
has the following properties: (i) the optimal order of addition of the reagents is
p-hydroxy phenylacetonitrile, 1,4-dioxane, ZnCl2, HCl gas, and finally 3,4-dihoxyl
phenol; (ii) HCl gas is not needed after the addition of 3,4-dimethoxyphenol; and
Scheme 2. Postulated mechanism in synthesis of 6,7,40-trihydroxyisoflavanone.

SYNTHESIS OF 6,7,40-TRIHYDROXYISOFLAVANONE
3299
(iii) up to 5% water in the reaction system does not affect the yield of deoxybenzoin.
This modified synthetic strategy enabled us to obtain deoxybenzoin on the kilogram
scale with a yield of 86% at room temperature.
Synthesis of 6,7-Dimethoxy-4’-hydroxyisoflavones (4)
The resulting deoxybenzoin was recarburized and cyclized to give 6,7-dimethoxy-
40-hydroxyisoflavones (4) in a 90% yield using DMF=PCl5 as a carbon atom donor in
the presence of BF3 ꢁ Et2O. As the mechanism of Vilsmeier–Haack reaction, the DMF=
þ
ꢂ
PCl5 mixture was the source of the [(Me2N CHCl) ]Cl reagent,[13] which rapidly
reacted with deoxybenzoin to form the intermediate 6. The intermediate was hydro-
lyzed in diluted hydrochloric acid solution at 85ꢀC for 2 h to give 6,7-dimethoxy-40-
hydroxyisoflavones. The postprocessing was simple (filtration), and the crude product
could be directly used in the next step and did not require further purification. This
synthetic sequence was suitable for the large-scale (ꢃ2 kg) preparation of the precursor
of 6,7,40-trihydroxyisoflavanone.
=
Synthesis of 6,7,4’-Trihydroxylisoflavanone
6,7,40-Trihydroxyisoflavanone was afforded by the deprotection of 3,4-
dimethoxy-40-hydroxyisoflavones. Many methods for O-demethylation, such as the
HBr–HOAc, Me3SiI, AlCl3=NaI, and H2SO4 methods, have been reported.[14]
owever, most of these methods are not very useful for large-scale reactions owing
to their poor yields or structural limitations. BBr3,[15] for instance, is a highly efficient
deprotection reagent, but the reaction must be performed under very rigorous
conditions (extremely low temperature). Grese et al.[16] reported that aromatic methyl
ethers could be easily cleaved upon treatment with AlC3=EtSH to give the parent
phenols. This new system for the deprotection of isoflavones has not been reported.
To reduce the toxicity and unpleasant smell from the ethanethiol, we used dimethyl
sulfide as the solvent. In the presence of AlC13=Me2S, the deprotection reaction
was completed at room temperature with a yield of 92%, and the reaction time was
less than 8 h. Therefore, large quantities of 6,7,40-trihydroxyisoflavanone were
obtained with a facile but cost-effective and highly efficient method.
Purification of 6,7,4’-Trihydroxylisoflavanone
Purification of 6,7,40-trihydroxyisoflavanone was investigated for obtaining
superpurified product. Thin-layer chromatography (TLC) analysis of the crude
product showed that the 6,7,40-trihydroxyisoflavanone was quite pure, and high-
performance liquid chromatography (HPLC) analysis showed its purity reached
96%. To increase the purity to more 99%, recrystallization of the crude product
was required. However, it is difficult to dissolve the compound in most single solvents,
such as water, methanol, ethanol, 1,4-dioxane, dichloromethane, acetone, ethyl
acetate, tetrahydrofuran (THF), and toluene; the exceptions are dimethylformamide
(DMF) and dimethylsulfoxide (DMSO). We tried and failed to purify the product in
mixed solvents, such as DMF=water and DMSO=water with various different
proportions. Eventually, we found that the 1,4-dioxane containing 10–40% water

3300
J. LIU ET AL.
could easily dissolve 6,7,40-trihydroxyisoflavanone at reflux. After the solution cooled,
white needle-like crystals of 6,7,40-trihydroxyisoflavanone were obtained. With this
method of recrystallization, the recovery of the product was 88%, and HPLC analysis
showed that the purity reached 99.5% (Fig. S7 in Supporting Information). The
1
structure of 6,7,40-trihydroxyisoflavanone was confirmed by H NMR, 13C NMR,
HRMS, IR, UV, and elemental analysis (EA) (Figs. S1–S6). We also analyzed the
residual solvents, and the results showed the total quantity of the residual solvents
did not exceed 0.02%. The quantity and purity of 6,7,40-trihydroxyisoflavanone allow
for further studies on its bioactivities and applications.
In conclusion, we used 3,4-dimethoxyphenol and p-hydroxy phenylacetonitrile
as the starting materials, and using a modified Houben–Hoesch reaction, cyclization,
and deprotection, we synthesized 6,7,40-trihydroxyisoflavanone. This reaction can be
scaled up to yield kilogram quantities under more facile conditions. The target
product was further recrystallized from 1,4-dioxane=H2O, after which the purity
reached 99.5%. The development of a method for the large-scale preparation of
6,7,40-trihydroxyisoflavanone with such high purity provides a solid basis for further
studies on this compound’s bioactivities and for drug development.
EXPERIMENTAL
3,4-Dimethoxyphenol (98.5%) and 4-hydroxybenzyl cyanide (99.0%) were
purchased from the Company of Astatech (ChengDu, China). All other chemicals
and solvents were analytical grade and used without further purification or dryness.
Reactions were monitored by thin-layer chromatography (TLC) on GF254 plates
(Qingdao Haiyang Chemical Group Co., Qingdao, China). Melting points were
determined on a Buchi B540 melting-point apparatus and were uncorrected. Infrared
spectra were measured with a Testscan FTIR-8000 Spectrophotometer. Ulraviolet
spectroscopy was recorded using a Shimadzu UV-3600 scanning spectrophotometer.
1
The H NMR spectra were recorded with a Varian 400-MHz NMR instrument in
either CDCl3 or DMSO-d6 with trimethylchlorosilane (TMS) as an internal stan-
dard. The NMR signals were described with symbols s for singlet, d for doublet, t
for triplet, and m for multiplet. Chemical shifts were reported in parts per million
ppm and coupling constants (J) are reported in hertz (Hz). HPLC analysis used
the conditions: column, Alltech Econosil C1810 U (22 ꢄ 250 mm, 5 mm particle size,
Alltech Associate, Inc., Deerfield, IL, USA); UV detection, 260 nm; flow rate,
1.0 ml=min; mobile phase, methanol=water (v=v, 40% methanol), and pH 3 controlled
by trifluoroacetic acid. HRMS were performed on a Bruker BioTOFIIIQ system and
reported as m=z (relative intensity). Elemental analysis was performed on a Carlo
Erba1106 instrument.
3,4-Dimethoxyl-4’-hydroxyl-deoxybenzoin (3)
To a mixture of anhydrous ZnCl2(2 kg, 14.7 mol) and 1,4-dioxane (6 L), dry HCl
gas was added until saturation, and the reaction mixture was stirred for 6 h at room
temperature. 4-Hydroxybenzyl cyanide (2) (2 kg, 15 mol) was added portionwise.
After 6 h, the 3, 4-dimethoxyphenol (1) (2 kg, 13 mol) was added portionwise. The mix-
ture was then stirred at room temperature for 20 h until the complete disappearance of

SYNTHESIS OF 6,7,40-TRIHYDROXYISOFLAVANONE
3301
the reagents, as shown by TLC. Then, the reaction mixture was poured into 100 L of
5% HCl dilute solution and stirred at 85 ꢀC for 1 h. The precipitate formed in reaction
was filtered, washed with warm water to neutral, and dried to obtain 3 (3.21 kg, yield
85%) with a purity of 96% (HPLC). Melting point: 174–175.5 ꢀC; 1H NMR (400 MHz,
DMSO) d ppm: 12.50 (1H, s, 2-OH), 9.32 (1H, s, 40-OH), 7.42 (1H, s, 6-H), 7.10 (2H,
d, J ¼ 8.0 Hz, 20,60-H), 6.71 (2H, d, J ¼ 8.0 Hz, 30,50-H), 6.55 (1H, s, 3-H), 4.22 (2H, s,
CH2), 3.82 (3H, s, 4-OMe), 3.76 (3H, s, 5-OMe); 13C NMR (100 MHz, DMSO) d ppm:
44.100, 56.205, 56.410, 100.731, 112.497, 115.538, 125.430, 130.735, 141.889, 156.380,
156.680, 159.567, 202.981.
6,7-Dimethoxyl-4’-hydroxylisoflavanone (4)
A mixture of 3 (2 kg, 7 mol) and DMF (12 L) was cooled to 0–10 ꢀC with stir-
ring, and then BF3Et2O (1.4 L) was added dropwise within 3 h. In another flask,
DMF (18 L) was cooled to 0–10 ꢀC and PCl5 (3 kg, 14.4 mol) was added portionwise.
The mixture was then allowed to stand at 55 ꢀC for 30 min and then added to the
reaction mixture slowly. During the addition, the temperature of the reaction mix-
ture was maintained below 27 ꢀC. The mixture was then stirred at room temperature
for 8 h, poured into 100 L of 10% HCl solution, and stirred at 85 ꢀC for another 2 h.
The precipitate formed in reaction was filtered, washed with warm water to neutral,
and dried to obtain 4 (1.864 kg, yield 90%) with a purity of 94% (HPLC). Melting
1
point: 232–234 ꢀC. H NMR (400 MHz, DMSO) d ppm: 9.561 (1H, s, 40-OH),
8.374 (1H, s, 2-H), 7.43 (1H, s, 5-H), 7.41 (2H, d, J ¼ 8.0 Hz, 2,6-H), 7.21 (1H, s,
8-H), 6.82 (2H, d, J ¼ 8.0 Hz, 3,5-H), 3.92 (3H, s, 6-OMe), 3.87 (3H, s, 7-OMe);
13C NMR (100 MHz, DMSO) d ppm: 55.937, 56.552, 100.436, 123.418, 130.345,
147.565, 151.904, 152.980, 154.357, 157.441, 174.579.
6,7,4’-Trihydroxylisoflavanone
A mixture of AlCl3 (8 kg, 60 mol) and CH2Cl2 (24 L) was cooled to 10 ꢀC with
strong stirring, and then CH3SCH3 (1.4 L, 34 mol) was added dropwise within 4 h.
Compound 4 (2 kg, 6.7 mol) was added portionwise to the reaction and stirred at
room temperature (10–30 ꢀC) for 8 h. Then the reaction mixture was poured into
120 L of 10% HCl solution and stirred for 2 h at room temperature. The reaction
was stopped and let stand for stratification. The upper solution was poured out,
and the residue precipitate was washed with 95% ethanol (16 L) to neutral and dried
to obtain crude product of 6,7,40-trihydroxylisoflavanone (1.667 kg, yield 92%) with a
purity of 96% (HPLC). The crude product was further purified by recrystallization
from 1,4-dioxane that contained 10–40% water. After the solution cooled, white
needle-like crystals of 6,7,40-trihydroxyisoflavanone were obtained. The recovery of
the product was 88%, and HPLC analysis showed that the purity reached 99.5%
1
(HPLC). Melting point: 322–323 ꢀC; H NMR (400 MHz, DMSO) d ppm: 10.40
(1H, br.s, OH-6), 9.80 (1H, br.s, OH-7), 9.52 (1H, br.s, OH-40), 8.25 (1H, s, H-2),
7.38 (1H, s, H-5), 7.37 (2H, d, H-2, H-60), 6.90 (1H, s, H-8), 6.80 (2H, d, J ¼ 8.0 Hz,
H-30H-50); 13C NMR (100 MHz, DMSO) d ppm: 103.035, 108.340, 115.187, 116.851,
1
122.989, 130.368, 144.903, 151.131, 152.499, 157.303, 174.697; H NMR and 13C
NMR in accordance with Ref. 17. HRMS (ESI) m=z: [MþNa]þ, calcd. for

3302
J. LIU ET AL.
C15H10NaO5: 293.0426; found 293.0409. UV (MeOH): kmax ¼ 257 nm; IR (KBr)
cmꢂ1: 3286.1 (Ar-OH), 1674 (6-C O), 832.8 (Ar-OH). Elemental analysis calcd.: C,
=
66.67; H, 3.70. Found: C, 66.56; H, 3.76.
FUNDING
We thank the National Natural Science Fund of China (No. 81172601 and
No. 81201195) for the financial support of this study.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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