Thallium(III) p-tosylate mediated oxidative 2,3-aryl rearrangement: A new useful route to ipriflavone and its analogs

Article abstract of DOI:10.1080/00397910802238734

A new route for the synthesis of ipriflavone, an antiosteoporotic agent, is described that has four steps and 60% yields starting from resacetophenone (2). The key step of the present methodology is thallium(III) p-tosylate mediated oxidative 2,3-aryl rearrangement of flavanone to generate the isoflavone ring system of ipriflavone in a highly efficient manner. Copyright Taylor & Francis Group, LLC.

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Thallium(III) p-Tosylate
Mediated Oxidative 2,3-Aryl
Rearrangement: A New Useful
Route to Ipriflavone and Its
Analogs
M. Muthukrishnan a & Om V. Singh a
a Phytochemistry Division, Tropical Botanic Garden
and Research Institute, Pacha-Palode , Trivandrum ,
Kerala , India
Published online: 20 Oct 2008.
To cite this article: M. Muthukrishnan & Om V. Singh (2008) Thallium(III) p-
Tosylate Mediated Oxidative 2,3-Aryl Rearrangement: A New Useful Route to
Ipriflavone and Its Analogs, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:22, 3875-3883, DOI:
10.1080/00397910802238734
To link to this article: http://dx.doi.org/10.1080/00397910802238734
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Synthetic Communications1, 38: 3875–3883, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238734
Thallium(III) p-Tosylate Mediated Oxidative
2,3-Aryl Rearrangement: A New Useful Route
to Ipriflavone and Its Analogs
M. Muthukrishnan and Om V. Singh
Phytochemistry Division, Tropical Botanic Garden and Research Institute,
Pacha-Palode, Trivandrum, Kerala, India
Abstract: A new route for the synthesis of ipriflavone, an antiosteoporotic agent,
is described that has four steps and 60% yields starting from resacetophenone (2).
The key step of the present methodology is thallium(III) p-tosylate mediated
oxidative 2,3-aryl rearrangement of flavanone to generate the isoflavone ring
system of ipriflavone in a highly efficient manner.
Keywords: Flavanones, ipriflavone, isoflavones, oxidative rearrangement,
thallium(III) p-tosylate
The isoflavones are a subclass of the flavonoids, which are mainly present
in the species of the Leguminosae family. Often they are called phytoalex-
ins because of their key role in plants’ defense against fungal infection.[1]
Moreover, these natural products have demonstrated numerous biologi-
cal activities such as estrogenic,[2] anticancer,[3] antibacterial,[4] antimicro-
bial,[5] antiulcer,[6] and protein tyrosine kinase inhibiting[7] activities.
Isoflavones are also called plant estrogens because they have positive
influences on the bone similar to the effect of estrogen, but although
estrogen has been associated with an increased risk of cancer, phyto-
estrogen can help to reduce the risk of cancer.[2] Based on these facts, ipri-
flavone (7-isopropyloxyisoflavone; 1a), a derivative of isoflavones
Received March 21, 2008.
Address correspondence to M. Muthukrishnan, (present address), Division of
Organic Chemistry, National Chemical Laboratory, Pune 411 008, India. E-mail:
m.muthukrishnan@ncl.res.in
3875

3876
M. Muthukrishnan and O. V. Singh
isolated from soy, was developed for the treatment of osteoprosis.[8]
Ipriflavone (Fig. 1) had been shown to increase the bone’s calcium
retention, inhibit bone breakdown, promote the activity of bone-building
cells, and reduce the pain of osteoporotic fractures.[9] It is registered as
a prescription drug for the treatment for osteoporosis in various
European countries and Japan with the trade names Iprosten, Osteofix,
and Osten.
The ipriflavone is synthesized by following three different routes. The
first route is the isopropylation of 7-hydroxyisoflavone using isopropyl
bromide or isopropyl sulphonate,[10] the second route is the addition of
the C1 unit to 40-isopropyloxy-20-hydroxydeoxybenzoin or 20,40-dihydrox-
ydeoxybenzoin by using trimethyl orthoformate under different reaction
conditions,[11] and the third is the treatment of acid chloride with enam-
ines under mild reaction condition.[12] We have developed a new route for
the synthesis of isoflavones by oxidative rearrangement of flavanone
using thallium(III) p-tosylate (TTS)[13] and thallium(III) perchlorate.[14]
To demonstrate the potential utility of this methodology, we synthesized
several isoflavones that possessed a natural substitution pattern, which
led to the synthesis of several naturally occurring isoflavones.[15] Herein,
we further extend the utility of thallium(III) p-tosylate for the synthesis of
ipriflavone, an antiosteoporotic agent, and its analogs.
The synthesis of ipriflavone (1a) is illustrated in Scheme 1. Isopropy-
lation of resacetophenone (2) with 2-bromopropane in the presence of
K2CO3 as a base afforded 2-hydroxy-4-isopropyloxyacetophenone (3)
in 95% yield.[16] The Claisen–Schmidt condensation of 3 with benzalde-
hyde in KOH-MeOH solution afforded 20-hydroxy-40-isopropyloxy-3-
phenyl-1-acrylophenone (4a) in 80% yield. Similarly, compounds 4b and
c were also synthesized from 3 by Claisen–Schmidt condensation with
p-anisaldehyde and piperonal in excellent yields. The isomerization–
cyclization of chalcone 4a to the corresponding 7-isopropyloxyflavanone
(5a) was achieved by heating the former in an acidic solution such as
hydrochloric acid in acetic acid or sulphuric acid in ethanol, but the yield
was very poor, probably because of the deprotection of the isopropyl
group, and 7-hydroxyflavanone was obtained as the major product.
Figure 1. Ipriflavone.

New Route to Ipriflavone
3877
Scheme 1. (a) R ¼ R1 ¼ H, Ipriflavone; (b) R ¼ OMe, R1 ¼ H; and (c) R,
R1 ¼ –OCH2O–. Reagents and conditions: (i) isopropyl bromide, K2CO3,
DMF, 80–90ꢀC; 12 h, 95%; (ii) aromatic aldehyde, KOH-MeOH, rt, 24 h,
75–85%; (iii) pyridine-MeOH-H2O (1:1:1), rreflux, 12 h, 80–90%; and (iv) TTS,
MeCN, reflux, 2 h, 92–94%.
Later, it was found that chalcone 4a can be easily cyclized to 7-isopropy-
loxyflavanone (5a) by refluxing it in a mixture of pyridine–methanol–
water (1:1:1) for 12 h in excellent yields. Similarly the chalcones 4b and
c were also cyclized to corresponding flavanones 5b and c by heating
the former in pyridine–methanol–water (1:1:1) for 12 h.
It was envisioned that the thallium(III) p-tosylate mediated oxidative
2,3-aryl rearrangement of flavanone to isoflavone developed by our
group[13–15] would provide a convenient access to ipriflavone if the meth-
odology works well with flavanone 5a. Therefore, 7-isopropyloxyflava-
none (5a) treated with thallium(III) p-tosylate in refluxing acetonitrile
for 2 h smoothly underwent oxidative 2,3-aryl rearrangement to afford
ipriflavone (1a) in excellent yield without deprotection of the isopropyl
group. The appearance of the characteristic H-2 proton of isoflavone
at d 7.94 as a singlet and the disappearance of flavanone signals in the
1
aliphatic region in the H NMR spectrum of 1a confirms the formation
of an isoflavone nucleus. Similarly, the oxidative 2,3-aryl
rearrangement induced by thallium(III) p-tosylate was successfully
applied to the synthesis of 7-isopropyloxy-40-methoxyisoflavone (1b)
and 7-isopropyloxy-30,40-methylenedioxyisoflavone (1c).
In summary, we have developed a new synthetic route to ipriflavone
by oxidative rearrangement of flavanone using thallium(III) p-tosylate in
four steps and 60% overall yields starting from resacetophenone. The
present methodology is also amenable to different substituents at aryl

3878
M. Muthukrishnan and O. V. Singh
ring C and would be useful to generate a large number of ipriflavone
derivatives.
EXPERIMENTAL
General
Melting points were taken in open capillaries in a sulfuric acid bath and
are uncorrected. IR spectra (nmax in cmꢁ1) were recorded on a Perkin-
Elmer 283 IR spectrophotometer; H NMR spectra were recorded on
1
Brucker DPX-200 using CDCl3 as solvent and residual solvent as the
internal standard. Thallium(III) acetate was purchased from Aldrich
Chemical Co. (USA), and thallium(III) p-tosylate was prepared from
thallium(III) acetate as described earlier.[17] All solvents were distilled
before use. Thin-layer chromatography (TLC) was performed on
silica-gel-coated glass plates and visualized in ultraviolet (UV) light
and=or staining with iodine. 2-Hydroxy-4-isopropyloxyacetophenone
(3) was synthesized by isopropylation of resacetophenone (2) in 95% yield
by a slightly modified procedure as described in the literature.[16]
20-Hydroxy-40-isopropyloxy-3-aryl-1-acrylophenones (3a-c),
General Procedure
Compound 2 (1.94 g, 10 mmol) and aromatic aldehyde (10 mmol) were
added to a solution of potassium hydroxide (1.23 g, 22 mmol) in
methanol (50 mL). The reaction mixture was stirred at room temperature
for 24 h and then neutralized with dilute hydrochloric acid and extracted
with dichloromethane (2 ꢂ 50 mL). The organic phase was washed with
saturated sodium bicarbonate solution (50 mL) followed by water
(50 mL) and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was chromatographed
over silica gel using petroleum ether–ethyl acetate (19:1) as eluent to
give 20-hydroxy-40-isopropyloxy-3-aryl-1-acrylophenones (3a–c). The
characterization data of 3a–c are given next.
Data for 3a–c
20-Hydroxy-40-isopropyloxy-3-phenyl-1-acrylophenone (3a)
Yellow crystalline solid; yield 2.26 g (80%); mp 91–92 ꢀC, IR (KBr)
1
n ¼ 3396 (OH), 1639 cmꢁ1 (>C ¼ O); H NMR (CDCl3): d 1.38 (d, 6H,

New Route to Ipriflavone
3879
J ¼ 6.0 Hz), 4.63 (m, 1H, J ¼ 6.0 Hz), 6.43–6.45 (m, 2H), 7.39–7.44 (m,
3H), 7.46 (d, 1H, J ¼ 15.3 Hz), 7.69 (m, 2H), 7.81 (d, 1H, J ¼ 9.6 Hz),
7.86 (d, 1H, J ¼ 15.3 Hz), 13.56 (s, 1H); HRMS: m=z ¼ 282.1254 (calcd.
for C18H18O3: 282.1256).
20-Hydroxy-40-isopropyloxy-3-(400-methoxyphenyl)-1-
acrylophenone (3b)
Yellow crystalline solid; yield 2.65 g (85%), mp 102–03 ꢀC; IR (KBr)
n ¼ 3400 (OH), 1641 cmꢁ1 (>C ¼ O); 1H NMR (CDCl3): d 1.37 (d,
6H, J ¼ 6.0 Hz), 3.86 (s, 3H), 4.63 (m, 1H), 6.43–6.45 (m, 2H),
6.95 (brd, 2H, J ¼ 8.7 Hz), 7.46 (d, 1H, J ¼ 15.4 Hz), 7.61 (brd,
2H, J ¼ 8.7 Hz), 7.81 (d, 1H, J ¼ 9.6 Hz), 7.86 (d, 1H, J ¼ 15.4 Hz),
13.52 (s, 1H); HRMS: m=z ¼ 312.1364 (calcd. for C19H20O4:
312.1362).
20-Hydroxy-40-isopropyloxy-3-(300,400-methylenedioxy)-1-
acrylophenone (3c)
Yellow crystalline solid: yield 2.45 g (75%); mp 123–24 ꢀC; IR (KBr)
1
n ¼ 3398 (OH), 1640 cmꢁ1 (> C ¼ O); H NMR (CDCl3): d 1.37 (d, 6H,
J ¼ 6.0 Hz), 4.63 (m, 1H), 6.04 (s, 2H), 6.43–6.45 (m, 2H), 6.86 (d, 1H,
J ¼ 8.0 Hz), 7.14 (dd, 1H, J ¼ 1.6 & 8.1 Hz), 7.18 (d, 1H, J ¼ 1.6 Hz),
7.46 (d, 1H, J ¼ 15.4 Hz), 7.81 (d, 1H, J ¼ 9.6 Hz), 7.86 (d, 1H,
J ¼ 15.4 Hz), 13.52 (s, 1H); HRMS: m=z ¼ 326.1150 (calcd. for
C19H18O5: 326.1154).
7-Isopropyloxyflavanones (4a–c), General Procedure
20-Hydroxy-40-isopropyloxy-3-aryl-1-acrylophenones (3a–c; 300 mg) was
dissolved in pyridine–methanol–water (1:1:1; 30 mL), and the reaction
mixture was refluxed for 12 h on a hot plate. After completion of the
reaction, it was cooled to room temperature, and the solvent was concen-
trated to 5 mL under reduced pressure. To this, water (50 mL) was added
and extracted with chloroform (2 ꢂ 25 mL). The organic phase was
washed with dilute hydrochloric acid and saturated sodium bicarbonate
solution followed by water and dried over anhydrous sodium sulfate.
The solvent was removed under reduced pressure, and the residue was
passed through a small bed of basic alumina using ethyl acetate–hexane
(1:10) as eluent to give 7-isopropyloxyflavanone (4a–c). The characteriza-
tion data of 4a–c are presented next.

3880
M. Muthukrishnan and O. V. Singh
Data for 4a–c
7-Isopropyloxyflavanone (4a)
White crystalline solid; yield 258 mg (86%); mp 132–33 ꢀC; IR (KBr)
1
n ¼ 1685 cmꢁ1 (>C ¼ O); H NMR (CDCl3): d 1.35 (d, 6H, J ¼ 6.0 Hz),
2.80 (dd, 1H, J ¼ 2.9 & 16.9 Hz), 3.05 (dd, 1H, J ¼ 12.5 & 16.9 Hz),
4.58 (m, 1H), 5.43 (dd, 1H, J ¼ 2.9 & 12.5 Hz), 6.44 (d, 1H,
J ¼ 2.3 Hz), 6.57 (dd, 1H, J ¼ 8.8 & 2.3 Hz), 7.35–7.51 (m, 5H), 7.85
(1H, d, J ¼ 8.8 Hz); HRMS: m=z ¼ 282.1257 (calcd. for C18H18O3:
282.1256).
7-Isopropyloxy-40-methoxyflavanone (4b)
Yield 240 mg (80%), mp 99–100 ꢀC; IR (KBr) n ¼ 1680 cmꢁ1 (> C ¼ O);
1H NMR (CDCl3): d 1.35 (d, 6H, J ¼ 6.0 Hz), 2.79 (dd, 1H, J ¼ 2.9 &
16.8 Hz), 3.05 (dd, 1H, J ¼ 13.3 & 16.8 Hz), 3.84 (s, 3H), 4.58 (m, 1H),
5.41 (dd, 1H, J ¼ 2.8 & 13.3 Hz), 6.43 (d, 1H, J ¼ 2.3 Hz, H-8), 6.57
(dd, 1H, J ¼ 8.8 & 2.4 Hz), 6.96 (brd, 2H, J ¼ 8.7 Hz), 7.46 (brd, 2H,
J ¼ 8.7 Hz), 7.85 (d, 1H, J ¼ 8.8 Hz); HRMS: m=z ¼ 312.1360 (calcd. for
C19H20O4: 312.1362).
7-Isopropyloxy-30,40-methylenedioxyflavanone (4c)
White crystalline solid, yield 270 mg (90%), mp 124–25 ꢀC, IR (KBr)
1
n ¼ 1688 cmꢁ1 (>C ¼ O); H NMR (CDCl3): d 1.35 (d, 6H, J ¼ 6.1 Hz),
2.78 (dd, 1H, J ¼ 2.9 & 16.8 Hz), 3.06 (dd, 1H, J ¼ 13.3 & 16.8 Hz),
4.58 (m, 1H), 5.42 (dd, 1H, J ¼ 2.9 & 13.3 Hz), 6.44 (d, 1H,
J ¼ 2.3 Hz), 6.57 (dd, 1H, J ¼ 8.8 & 2.4 Hz), 6.83 (d, 1H, J ¼ 8.0 Hz),
6.92 (dd, 1H, J ¼ 8.2 & 1.7 Hz), 7.01 (d, 1H, J ¼ 1.6 Hz), 7.85 (d,
1H, J ¼ 8.9 Hz); HRMS: m=z ¼ 326.1151 (calcd. for C19H18O5:
326.1154).
7-Isopropyloxyisoflavones (1a–c), General Procedure
Thallium(III) p-tosylate (800 mg, 1.1 mmol) was added to a solution of
7-isopropyloxyflavanone (4a–c; 1 mmol) in acetonitrile (15 mL), and the
resulting mixture was refluxed for 2 h. The reaction mixture was cooled
to room temperature and diluted with dichloromethane (50 mL), and
the separated thallium(I) p-tosylate was filtered off and washed with
dichloromethane (20 mL). The filtrate was washed with saturated

New Route to Ipriflavone
3881
aqueous solution of sodium hydrogen carbonate (2 ꢂ 50 mL), followed by
water, and dried over anhydrous sodium sulfate. The solvent was then
distilled off under reduced pressure, and the residue was passed over a
small bed of basic alumina and recrystallized from ethyl acetate–hexane
(1:9) to afford 7-isopropyloxyisoflavones (1a–c). The characterization
data of 1a–c are given next.
Data for 1a–c
Ipriflavone [7-Isopropyloxyisoflavone (1a)]
White crystalline solid: yield 258 mg (92%); mp 114–15 ꢀC (lit.[12] mp 115–
117 ꢀC), IR (KBr) n ¼ 1640 cmꢁ1 (>C ¼ O); 1H NMR (CDCl3): d 1.41 (d,
6H, J ¼ 6.0 Hz), 4.68 (m, 1H), 6.86 (d, 1H, J ¼ 2.2 Hz), 6.96 (dd, 1H,
J ¼ 2.2 & 8.9 Hz), 7.32–7.48 (m, 3H), 7.52–7.60 (m, 2H), 7.94 (s, 1H),
8.21 (d, 1H, J ¼ 8.9 Hz).
7-Isopropyloxy-40-methoxyisoflavone (1b)
White crystalline solid; yield 291 mg (94%); mp 149–51 ꢀC; IR (KBr)
1
n ¼ 1639 cmꢁ1 (>C ¼ O); H NMR (CDCl3): d 1.41 (d, 6H, J ¼ 6.0 Hz),
3.84 (s, 3H), 4.67 (m, 1H), 6.83 (d, 1H, J ¼ 2.0 Hz), 6.92–6.99 (m, 3H),
7.50 (brd, 2H, J ¼ 8.7 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J ¼ 8.9 Hz); HRMS:
m=z ¼ 310.1202 (calcd. for C19H18O4: 310.1205).
7-Isopropyloxy-30,40-methylenedioxyisoflavone (1c)
White crystalline solid; yield 305 mg (94%), mp 154–55 ꢀC, IR (KBr)
1
n ¼ 1638 cmꢁ1 (>C ¼ O); H NMR (CDCl3): d 1.41 (d, 6H, J ¼ 6.0 Hz),
4.67 (m, 1H), 5.99 (s, 2H), 6.83 (d, 1H, J ¼ 2.2 Hz), 6.87 (d, 1H, J ¼ 8.0 Hz),
6.94–6.99 (m, 2H), 7.10 (d, 1H, J ¼ 1.4 Hz), 7.90 (s, 1H), 8.19 (d, 1H,
J ¼ 8.9 Hz); HRMS: m=z ¼ 324.0996 (calcd. for C19H16O5: 324.0998).
ACKNOWLEDGMENTS
The authors are grateful to the International Foundation of Science,
Sweden, and the State Committee on Science, Technology, and
Environment, Thiruvananthapuram, Government of Kerala, India,
for financial support.

3882
M. Muthukrishnan and O. V. Singh
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oxidation
of