An efficient synthesis of daidzein, dimethyldaidzein, and isoformononetin

Article abstract of DOI:10.1016/j.tetlet.2010.06.078

Synthesis of the soy isoflavone, daidzein, and its derivatives, isoformononetin and dimethyldaidzein, through utilization of a novel synthetic pathway is reported. This synthesis employs an enamine addition and O-methylation of 2,4-dihydroxyacetophenone, a subsequent ring closure and iodination, followed by a Suzuki coupling with PEG 10000. Demethylation of either isoformononetin or dimethyldaidzein afforded daidzein.

Full text of DOI:10.1016/j.tetlet.2010.06.078

Tetrahedron Letters 51 (2010) 4408–4410
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Tetrahedron Letters
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An efficient synthesis of daidzein, dimethyldaidzein, and isoformononetin
*
Kyle F. Biegasiewicz, Jeffrey D. St. Denis, Vincent M. Carroll, Ronny Priefer
Department of Chemistry, Biochemistry, and Physics, Niagara University, NY 14109, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of the soy isoflavone, daidzein, and its derivatives, isoformononetin and dimethyldaidzein,
through utilization of a novel synthetic pathway is reported. This synthesis employs an enamine addition
and O-methylation of 2,4-dihydroxyacetophenone, a subsequent ring closure and iodination, followed by
a Suzuki coupling with PEG 10000. Demethylation of either isoformononetin or dimethyldaidzein affor-
ded daidzein.
Received 18 May 2010
Revised 7 June 2010
Accepted 14 June 2010
Available online 19 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
O
OH
OH
O
Flavonoids are a class of natural products that are composed of
a three ring backbone, two of which are aryl moieties. They are a
key contributor in a series of plant defense mechanisms acting as
free-radical scavengers throughout the body.1 The flavonoids
encompass six subclasses including the flavones, flavonols, flava-
nones, isoflavones, anthocyanidins, and catechins.2 One flavonoid
subclass that has received a great deal of attention over the last
decade for potential biological and medicinal applications is the
isoflavones.
Soy isoflavones are found in the legume family of plants and
typically exist in a 7-O-glycosylated state until being metabolized
into aglycones.3 Some of the most popular isoflavones include
glycitein, genistein, formononetin, biochanin A (Fig. 1), and daidz-
ein, 1 (Fig. 2). Of these, the most extensive studies have been fo-
cused on genistein and daidzein.4
O
HO
O
HO
HO
O
Glycitein
Genistein
O
O
O
O
O
HO
O
Formononetin
Biochanin A
Figure 1. Common isoflavones found in soybeans.
OH
O
Daidzein has gained particular interest in recent years for its
biological applications. It functions much like genistein, in terms
of its strong antioxidant activity and its estrogen-like structure
allowing for altered growth, development, and function of estro-
gen-dependant target tissues,5 but in addition, daidzein also has
its own unique capabilities. It has been shown to elevate the activ-
ity of catalase, superoxide dismutase, glutathione peroxidase, and
glutathione reductase in the skin and small intestine,5 and inhibit
osteoporosis in ovariectomized mice.6 In addition, at low concen-
trations daidzein has demonstrated its ability to stimulate cate-
cholamine synthesis through estrogen receptors,7 and inhibit
CYP1A1 in mouse hepatoma cell cultures showing a reduction in
carcinogenesis.8 Finally, it has been shown to be a potential
treatment for neurodegeneration,9 and has been proven to be more
efficient than genistein in preventing ovariectomy-induced osteo-
porosis in rats.10
HO
O
1
Figure 2. Structure of daidzein.
Multiple syntheses have been carried out to produce daidzein. It
has been recently prepared by initially producing 4-benzyloxysal-
icylaldehyde from resorcinol. A Wittig reaction, O-alkylation, an
additional Wittig, RCM with Grubb’s catalyst, subsequent hydrob-
oration–oxidation to create the chromen ring, treatment with DDQ
in an oxidation–dehydration reaction, and finally debenzylation
and demethylation with AlCl3/EtSH gave daidzein.11 Other proce-
dures have also been employed including utilization of resorcinol,
4-hydroxyphenylacetic acid, and BF3-Et2O to form a phenyl–benzyl
ketone and subsequently to form daidzein in a reaction with Me-
SO2Cl, BF3-Et2O, and DMF.12 It has also been demonstrated that
* Corresponding author. Tel.: +1 716 286 8261; fax: +1 716 286 8254.
E-mail address: rpriefer@niagara.edu (R. Priefer).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.078

K. F. Biegasiewicz et al. / Tetrahedron Letters 51 (2010) 4408–4410
4409
OH
O
O
O
O
O
O
I
(ii)
(iiia)
N
(i)
5a
O
OH
HO
OH
O
O
3
4
2
(iiib)
(iv)
OH
O
O
O
O
O
(iv)
HO
O
1
5b
Scheme 1. Synthetic path to the isoflavones, isoformononetin, dimethyldaidzein, and daidzein. Reagents and conditions: (i) DMF-DMA, DMF, 80 °C, 24 h; (ii) I2, MeOH, rt,
24 h; (iiia) 4-OH-PBA, Na2CO3, Pd(OAc)2, PEG 10000, 50 °C, MeOH, 3 h; (iiib) 4-OMe-PBA, Na2CO3, Pd(OAc)2, PEG 10000, 50 °C, MeOH, 3 h; (iv) HI, reflux, 4 h.
by using benzyl-protected acetophenones and running aldol con-
densation with 4-methoxybenzaldehyde, treatment with thallium
nitrate for oxidative rearrangement, followed by addition of hydro-
chloric acid affords daidzein.13
Herein, we report an efficient, novel synthetic pathway to yield
daidzein, as well as its derivatives, isoformononetin and dimeth-
yldaidzein. This was accomplished through the utilization of an en-
amine addition and O-methylation, a ring closure and iodination, a
Suzuki coupling with PEG 10000, and O-demethylation to afford
our desired product, daidzein.
It has been demonstrated by Stevens and co-workers that N,N-
dimethylformamide dimethylacetal (DMF-DMA) can be used with
acetophenone derivatives to yield enamino-ketones.14 Our synthe-
sis (Scheme 1) began with commercially available 2,4-dihydroxy-
acetophenone (2) and DMF-DMA. Our original intention was
strictly to add the enamine moiety to the starting acetophenone,
but upon stirring at 80 °C in DMF for 24 h, we found that it went
through an additional O-methylation on the 4-OH group, resulting
in 3-dimethylamino-1-(2-hydroxy-4-methoxy)-phenylpropenone
(3) in a respectable yield of 89%.15 It has also been demonstrated
that DMF-DMA is capable of O-methylation of phenols.16 We made
multiple attempts to isolate the non-O-methylated enamine prod-
uct by performing the reaction with 1:1, 1:2, and 1:3 ratios of
2:DMF-DMA as well as at various temperatures. Only the 1:2 ratio
at 80 °C was determined mildly successful but still afforded >60%
of 3. Attempted isolation of the desired non-O-methylated product
was very difficult due to its insolubility in ethyl acetate, chloro-
form, dichloromethane, and hexanes. The compound was finally
determined to be soluble in acetonitrile and attempted recrystalli-
zation yielded very little product. As a result, we continued the
synthesis conscious of the final O-demethylation step.
men-4-one) (5b, 90%).21 The PEG/Pd(OAc)2 could also be reused
without the further addition of palladium.
Our final step required the demethylation of 5a and 5b to yield
our desired product, daidzein, 1. A series of demethylation tech-
niques utilizing BBr3, BCl3,22 AlCl3,23 and trimethylsilyl iodide
(TMSI)24 were initially attempted on both derivatives. The only
method that was mildly effective was the use of TMSI because of
its ability to demethylate the 40-OMe on the dimethyldaidzein
derivative after one week at reflux in chloroform solvent. The
method that proved effective for both derivatives involved dissolv-
ing the respective daidzein derivative in HI and maintaining it at
reflux for 4 h.25 Once the product was collected and subjected to
silica gel chromatography, we obtained our desired product, daidz-
ein, in high yields (isoformononetin—89%, dimethyldaidzein—
94%).26
In conclusion, a novel pathway has been demonstrated for the
synthesis of daidzein, through either isoformononetin or dimeth-
yldaidzein in four steps, with an overall yield of 62% and 61%,
respectively.
Acknowledgments
The authors would like to thank the Niagara University Aca-
demic Center for Integrated Science and the Rochester Academy
of Science for the financial support.
References and notes
1. Li, M.; Han, X.; Yu, B. J. Org. Chem. 2003, 68, 6842.
2. Song, J.; Kwon, O.; Chen, S.; Daruwala, R.; Eck, P.; Park, J. B.; Levine, M. J. Biol.
Chem. 2002, 277, 15252.
3. Phillips, D.; Kapulnik, Y. Trends Microbiol. 1995, 3, 58.
4. Chen, J.; Wang, S. Drug Metab. Dispos. 2005, 33, 1777.
5. Liu, H.; Zhang, C.; Zeng, W. Domest. Anim. Endocrinol. 2005, 31, 258.
6. Fujioka, M.; Uehara, M.; Wu, J.; Adlercreutz, H.; Suzuki, K.; Kanazawa, K.;
Takeda, K.; Yamada, K.; Ishimi, Y. J. Nutr. 2004, 134, 2623.
7. Liu, M.; Yanagihara, N.; Toyohira, Y.; Tsutsui, M.; Ueno, S.; Shinohara, Y.
Endocrinology 2007, 148, 5348.
8. Shertzer, H.; Puga, A.; Chang, C.; Smith, P.; Nebert, D. W.; Setchell, D. R.; Dalton,
T. P. Chem. Biol. Interact. 1999, 123, 31.
9. Mao, Z.; Zheng, Y.; Zhang, Y.; Han, B.; Zhu, X.; Chang, Q.; Hu, X. Molecules 2007,
12, 1455.
10. Picherit, C.; Coxam, V.; Bennetau-Pelissero, C.; Kati-Coulibaly, S.; Davicco, M.;
Lebecque, P.; Barlet, J. J. Nutr. 2000, 130, 1675.
11. Li, S.; Chen, P.; Chen, L. Tetrahedron Lett. 2009, 50, 2121.
12. Yeap, G.; Yam, W.; Ito, M. Liq. Crystallogr. 2007, 34, 649.
13. Dung, S.; Cho, S.; Dang, T. Eur. J. Med. Chem. 2003, 38, 537.
14. Vasselin, D.; Westwell, A.; Matthews, C.; Bradshaw, T. D.; Stevens, M. F. G. J.
Med. Chem. 2006, 49, 3973.
15. Synthesis of 3-dimethylamino-1-(2-hydroxy-4-methoxy)-phenylpropenone (3):
2,4-Dihydroxyacetophenone (2, 3.00 g, 0.0197 mol) was dissolved into DMF
(150 mL) and warmed to 74 °C in an oil bath. Subsequently, DMF-DMA (9.67 g,
0.0812 mol) was added to the flask dropwise. The resulting mixture was stirred
for 24 h then cooled to room temperature. After quenching with water
As did Stevens et al.,14 our synthesis continued with a ring clo-
sure and iodination of our enamine added product, 3. Methylation
of the 4-OH group in the first step did not hinder a successful ring
closure and iodination of our enamine added product, 7-methoxy-
3-iodo-4H-chromen-4-one (4) in an 81% yield.17 This was followed
by a Suzuki coupling to afford daidzein derivatives, isoformonone-
tin (5a) or dimethyldaidzein (5b) when using the respective phen-
ylboronic acid (PBA) derivatives.14 A typical Suzuki coupling
involves the use of a phosphine-based ligand which can be toxic,
expensive, and difficult to separate from the reaction mixture.18
Liu et al. have recently demonstrated a green approach to this reac-
tion. The use of poly(ethylene glycol) 4000 (PEG 4000) as the li-
gand, along with Pd(OAc)2, Na2CO3, in H2O or MeOH effectively
gave the desired Suzuki products.19 In lieu of PEG 4000, we em-
ployed PEG 10000,20 which did indeed afford isoformononetin
(7-methoxy-3-(4-hydroxyphenyl)-4H-chromen-4-one) (5a, 98%)
and dimethyldaidzein (7-methoxy-3-(4-methoxyphenyl)-4H-chro-

4410
K. F. Biegasiewicz et al. / Tetrahedron Letters 51 (2010) 4408–4410
(200 mL), extracting with Et2O (5 ꢀ 120 mL), washing with H2O (100 mL),
through the solid. The ethereal extract was concentrated under reduced
pressure to yield an off-white solid which was subjected to silica gel
drying with MgSO4, and concentrating under reduced pressure, afforded a dark
green solid. The resulting solid was subjected to silica gel chromatography
chromatography
(3:1
hexanes/EtOAc)
yielding
7-methoxy-3-(4-
(ethyl
acetate)
yielding,
3-dimethylamino-1-(2-hydroxy-4-methoxy)-
hydroxyphenyl)-4H-chromen-4-one (5a: 0.347 g, 0.00129 mol, 98%), as a
phenylpropenone (3: 3.87 g, 0.0175 mol, 89%), as a bright green solid.
Rf = 0.74 (EtOAc).
white solid.
Rf = 0.43 (3:1 hexanes/EtOAc).
Mp = 198–201 °C.
Mp = 130–133 °C.
1H NMR (400 MHz, CDCl3) d = 7.84 (d, 1H, J = 12.0 Hz, CH@CH), 7.61 (d, 1H,
J = 9.2 Hz, Ar-H), 6.41 (d, 1H, J = 2.4 Hz, Ar-H), 6.38 (dd, 1H, J = 2.4, 9.2 Hz, Ar-
H), 5.68 (d, 1H, J = 12.0 Hz, CH@CH), 3.82 (s, 3H, –OCH3), 3.18 (s, 3H, –NCH3),
2.96 (s, 3H, –NCH3).
1H NMR (400 MHz, DMSO) d = 9.55 (s, 1H, –OH), 8.38 (1H, olefinic H), 8.03 (d,
1H, J = 8.4 Hz, Ar-H), 7.40 (d, 2H, J = 8.8 Hz, phenyl-H), 7.16 (d, 1H, J = 2.4 Hz,
Ar-H), 7.08 (dd, 1H, J = 2.4, 8.4 Hz, Ar-H), 6.81 (d, 2H, J = 8.8 Hz, phenyl-H), 3.91
(s, 3H, –OCH3).
13C NMR (100 MHz, CDCl3) d = 190.6, 165.5, 164.3, 154.0, 129.7, 113.8, 106.4,
101.0, 89.8, 55.4, 45.4, 37.4.
13C NMR (100 MHz, DMSO) d = 174.7, 163.7, 157.5, 157.3, 153.2, 130.1, 127.0,
123.7, 122.3, 117.6, 115.0, 114.8, 100.6, 56.1.
HR-MS (ESI) calculated for (M+H+): 222.1125, found: 222.11183.
16. Sinkevich, Y.; Shchekotikhin, A.; Luzikov, Y. Chem. Heterocycl. Compd. 2007, 43,
1252.
HR-MS (ESI) calculated for (M+H+): 269.0808, found: 269.08115.
Compound 5b: (0.264 g, 0.000934 mol, 90%), as a white solid.
Rf = 0.66 (3:1 hexanes/ethyl acetate).
17. Synthesis of methoxy-3-iodo-4H-chromen-4-one (4):
A
reaction flask was
Mp = 138–141 °C.
charged with 3-dimethylamino-1-(2-hydroxy-4-methoxy)-phenylpropenone
(3: 0.930 g, 0.00420 mol), iodine (1.611 g, 0.00635 mol), and methanol
(110 mL) and stirred at room temperature for 24 h. Methanol was removed
to yield a red-black residue that was treated with satd Na2SO3 to remove latent
iodine until the mixture was clear. The mixture was extracted with CHCl3
(3 ꢀ 50 mL), dried with MgSO4, and concentrated under reduced pressure to
give an off-white solid, which was subjected to silica gel chromatography (3:1
hexanes/EtOAc) yielding 7-methoxy-3-iodo-4H-chromen-4-one (4: 1.192 g,
0.00392 mol, 81%) as a white solid.
1H NMR (400 MHz, CDCl3) d = 8.22 (d, 1H, J = 8.8 Hz, Ar-H), 7.93 (s, 1H, olefinic
H), 7.51 (d, 2H, J = 8.0 Hz, phenyl-H), 7.00 (dd, 1H, J = 1.2, 8.8 Hz, Ar-H), 6.98 (d,
2H, J = 8.0 Hz, phenyl-H), 6.86 (d, 1H, J = 1.2 Hz, Ar-H), 3.92 (s, 3H, –OCH3), 3.85
(s, 3H, –OCH3).
13C NMR (400 MHz, CDCl3) d = 175.9, 163.9, 159.5, 157.9, 152.0, 130.1, 127.8,
124.9, 124.2, 118.4, 114.5, 113. 9, 100.1, 55.8, 55.3.
HR-MS (ESI) calculated for (M+H+): 283.0965, found: 283.09656.
22. Al-Maharik, N.; Botting, N. Tetrahedron 2004, 60, 1637.
23. Faria, T.; Silva, L.; Filho, J.; Chiari, E.; Oliveira, A. B. J. Braz. Chem. Soc. 2005, 16,
1415.
Rf = 0.54 (3:1 hexanes/EtOAc).
Mp = 161–164 °C.
24. Jung, M.; Lyster, M. J. Org. Chem. 1977, 42, 3761.
25. Shriner, R. L.; Hull, C. J. J. Chem. Soc. 1945, 228.
26. General procedure for demethylation: A reaction flask was charged with 7-
1H NMR (400 MHz, CDCl3) d = 8.22 (s, 1H, olefinic H), 8.15 (d, 1H, J = 8.8 Hz, Ar-
H), 7.00 (dd, 1H, J = 2.4, 8.8 Hz, Ar-H), 6.84 (d, 1H, J = 2.4 Hz, Ar-H), 3.91 (s, 3H,
OCH3).
methoxy-3-(4-hydroxyphenyl)-4H-chromen-4-one
(5a,
0.125 g,
13C NMR (100 MHz, CDCl3) d = 172.6, 164.3, 157.9, 157.2, 128.1, 115.7, 115.3,
100.0, 87.1, 55.9.
0.000462 mol) and HI (5 mL) and held at reflux for 4 h. Upon cooling, 30%
KOH (3 mL) was added and the resulting mixture was stirred for an additional
15 min. Subsequently, concd HCl (3 mL) was added forming a precipitate. The
resulting mixture was vacuum filtered and a red-brown solid was collected.
The solid was subjected to silica gel chromatography (3:2 EtOAc/hexanes)
affording daidzein (1, 0.105 g, 0.000410 mol, 89%) as a white solid.
Rf = 0.57 (3:2 EtOAc/hexanes).
HR-MS (ESI) calculated for (M+H+): 302.9513, found: 302.95090.
18. Ren, L.; Meng, L. Express Poly. Lett. 2008, 2, 251.
19. Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem. 2005, 70, 6122.
20. St. Denis, J. D.; Gordon, J. S., IV; Carroll, V. M.; Priefer, R. Synthesis 2010, 1590.
21. General procedure for Suzuki coupling: A round bottom flask was charged with
methanol (8.60 g) and Na2CO3 (0.354 g, 0.00285 mol) and allowed to stir. PEG
10000 (9.95 g) was ground to fine consistency and added to the flask with
Pd(OAc)2 (0.0326 g, 0.0001 mol). The reaction mixture with attached
condenser was then warmed to 50 °C in a water bath. Once the mixture
turned black, 7-methoxy-3-iodo-4H-chromen-4-one (4: 0.402 g, 0.00132 mol)
and 4-hydroxyphenylboronic acid (0.275 g, 0.00200 mol) were added and left
to stir for 3 h. Et2O (100 mL) was added, and the resulting mixture was emptied
into a Büchner funnel, and an additional aliquot of Et2O (200 mL) was run
Mp = 315–318 °C.
1H NMR (400 MHz, DMSO) d = 10.90 (s, 1H, –OH), 9.63 (s, 1H, –OH), 8.34 (s, 1H,
olefinic H), 8.00 (d, 1H, J = 8.8 Hz, Ar-H), 7.41 (d, 2H, J = 8.4 Hz, phenyl-H), 6.97
(dd, 1H, J = 2.0, 8.8 Hz, Ar-H), 6.90 (d, 1H, J = 2.0 Hz, Ar-H), 6.84 (d, 2H,
J = 8.4 Hz, phenyl-H).
13C NMR (100 MHz, DMSO) d = 175.7, 163.5, 158.4, 158.1, 153.8, 131.1, 128.3,
124.4, 123.5, 117.6, 116.1, 115.9, 103.1.
HR-MS (ESI) calculated for (M+H+): 255.0652, found: 255.06479.