Microwave-promoted synthesis of polyhydroxydeoxybenzoins in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2006.09.069

A microwave-promoted synthesis of polyhydroxydeoxybenzoins and -phenylpropanones has been developed, using bis{(trifluoromethyl)sulfonyl}amine (HNTf₂) or BF₃·OEt₂ in an ionic liquid solvent.

Full text of DOI:10.1016/j.tetlet.2006.09.069

Tetrahedron Letters 47 (2006) 8375–8378
Microwave-promoted synthesis of polyhydroxydeoxybenzoins
in ionic liquids
Ullastiina Hakala and Kristiina Wa¨ha¨la¨*
Laboratory of Organic Chemistry, Department of Chemistry, PO Box 55, FIN-00014, University of Helsinki, Finland
Received 7 July 2006; revised 4 September 2006; accepted 15 September 2006
Available online 6 October 2006
Abstract—A microwave-promoted synthesis of polyhydroxydeoxybenzoins and -phenylpropanones has been developed, using
bis{(trifluoromethyl)sulfonyl}amine (HNTf2) or BF3ÆOEt2 in an ionic liquid solvent.
Ó 2006 Elsevier Ltd. All rights reserved.
Microwave irradiation as an energy source provides a
powerful tool for synthetic work. Under microwave
heating of dipolar or ionic solvent mixtures, the energy
can be transferred to the reaction media via two mecha-
nisms—dipole rotation and ionic conduction. The use of
ionic liquids as solvents therefore makes them highly
suitable media for energy transfer as both mechanisms
for energy absorption can operate.1
nones, and no deoxybenzoins, hydroxy substituted or
otherwise, appear to have been studied.
We report here the synthesis of polyhydroxy-
deoxybenzoins using various ionic liquid reaction media
under microwave irradiation.
The activity of various ionic liquid/acidic additive
systems was assessed in the synthesis of 2,4,40-trihydr-
oxydeoxybenzoin 1 (Scheme 1, Table 1). In addition to
the additive, 1-butyl-3-methylimidazolium chloride–
indium(III) chloride ([bmim]Cl–InCl3) and HNTf2,
BF3ÆOEt2 was also included, even though the reagent
cannot be recycled after isolation of the product. How-
ever, BF3ÆOEt2 in [bmim][BF4] (entry 5) showed the
highest conversion and isolated yield although in order
to achieve complete reaction it was necessary to use it
in a stoichiometric amount. Comparable yields were
also obtained using a substoichiometric amount of the
Brønsted acid HNTf2 in [bmim][NTf2] (entry 2).
Co(NTf2)2, in either solvent, gave only marginally
higher yields than the reactions with no catalyst at
all (10–20%).
Recently, certain polyhydroxydeoxybenzoins (1,2-diaryl-
ethanones) were reported to possess considerable
selectivity and transcriptional bias towards the estrogen
receptor b, and were considered to constitute a promis-
ing new class of ERb-biased phytoestrogens.2 Deoxy-
benzoins are traditionally produced by the laborious
and time-consuming Hoesch reaction, where HCl gas
is bubbled into the reaction mixture for several hours.3
Although other methods exist for the synthesis of deoxy-
benzoins, they are not generally applicable to the poly-
hydroxy derivatives unless protection/deprotection
sequences are used.4
Friedel–Crafts (FC) acylation in ionic liquid (IL) sol-
vents has been extensively studied,5 using catalysts such
as chloroaluminate-,6 chloroferrate-7 and chloroindate-
ILs,8 zeolites,9 triflate salts,10 bismuth derivatives,11
HNTf2 or metal sulfonamides.12 The product ketones
were simple representative acetophenones or benzophe-
The use of 0.5 molar equiv of [bmim][NTf2] gave optimal
yields of compound 1 as higher ratios interfered with
HOOC
HO
IL + additive
MW
OH
HO
OH
+
Keywords: Microwave; Friedel–Crafts reaction; Ionic liquids;
Polyhydroxydeoxybenzoins.
O
OH
OH
Scheme 1. Synthesis of 2,4,40-trihydroxydeoxybenzoin 1.
*
Corresponding author. Tel.: +358
9 19150356; fax: +358 9
19150357; e-mail: kristiina.wahala@helsinki.fi
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.069

8376
U. Hakala, K. Wa¨ha¨la¨ / Tetrahedron Letters 47 (2006) 8375–8378
Table 1. Comparison of different reaction media in the synthesis of 2,4,40-trihydroxydeoxybenzoin (Scheme 1)13
Entry
Solvent/additive, ratioa
T (°C)
t (min)
Yield (%) (conversion by 1H NMR)
1
2
3
4
5
[bmim]Cl–InCl3, 0.6:2.0
100
90
100
120
100
6
4
60 (67)
73 (85)
70 (85)
30 (40)
88 (93)
[bmim][NTf2]/HNTf2, 0.5:0.3
[bmim][NTf2]/HNTf2, 0.5:0.3
[bmim][BF4]/HNTf2, 1:0.3
[bmim][BF4]/BF3ÆOEt2, 2:1
120b
4
4
a Relative to 1 equiv of substrate.
b Conventional heating.
Table 2. HNTf2 Mediated synthesis of polyhydroxydeoxybenzoins, O-demethylangolensin 6 and polyhydroxyphenylpropanone 7
R4
HO
OH
O
HO
OH
HNTf2
+
R3
R2
[bmim][NTf2]
R3
R1
R1
R2
MW 4 min.
Entry
Starting materials
R3
Yield (%) (conversion
by 1H NMR)
Product
R1
H
R2
R4
HO
OH
1a
OMe
H
COOH
74 (85)
O
OMe 2
HO
HO
OH
2a
H
OH
OMe
H
COOH
CN
70 (74)
OMe
OH
O
3
OH
3b
OH
OMe
73 (88)c
OH
O
OMe
OH
4
HO
HO
OH
4b
OH
OH
H
CN
65 (77)c
55 (70)
OH
O
5
COOH
OH
HO
HO
OH
OH
5a
+
O
OH
6
OH
COOH
HO
OH
O
OH
+
6a
60 (75)
7
OH
a [bmim][NTf2]/HNTf2 0.5:0.5, at 90 °C.
b [bmim][NTf2]/HNTf2 0.5:1.0, at 90 °C.
c Conversion by 1H NMR to the intermediate imino compound.
isolation procedures. The mechanism of action of HNTf2
in FC reactions probably depends on its superacidic
nature, as previously stated in similar cases in the litera-
ture.14 When the solvent was changed to [bmim][BF4]
(entry 4), HNTf2 probably reacted with the ionic liquid,
undergoing anion exchange, which produced a less acidic
solution, and thus reduced the reaction rate. The
[bmim]Cl–InCl3 system (entry 1) appeared to be less
active possibly due to the hydrophilicity of the ionic liquid.
However, isolation and purification of the compound
from chloroindate(III) ionic liquid was straightforward
and no additional purification was required.
Additional polyhydroxydeoxybenzoins were readily
prepared from arylacetic acids and resorcinols by HNTf2
or BF3ÆOEt2 catalysis as shown in Tables 2 and 3. A

U. Hakala, K. Wa¨ha¨la¨ / Tetrahedron Letters 47 (2006) 8375–8378
8377
Table 3. BF3ÆOEt2 Mediated synthesis of polyhydroxydeoxybenzoins and a polyhydroxyphenylpropanone in [bmim][BF4]
COOH
HO
R1
OH
O
.
HO
R1
OH
BF3 OEt2
+
[bmim][BF4]
MW 4 min.
R2
R2
R3
R3
Entry
Starting materials
R2
Yield (%)
Product
R1
R3
HO
OH
O
8
1a
OMe
H
OH
85
MeO
OH
2a
3a
H
H
OH
OH
OH
67
54
5
4
OMe
COOH
OMe
HO
OH
OH
HO
OH
4b
88
OMe
O
9
OH
a [bmim][BF4]/BF3ÆOEt2 4:2, at 90 °C.
b [bmim][BF4]/BF3ÆOEt2 2:1, at 90 °C.
Hoesch-type reaction using arylacetonitriles gave 2,4,6-
trihydroxy-40-methoxy- and 2,4,6,40-tetrahydroxydeoxy-
benzoins (4 and 5, respectively) in ionic solvent. The
intermediate imino compound was hydrolysed by the
addition of aqueous acid to the reaction medium. The
homologous 1,2- and 1,3-diarylpropanones 6, 7 and 9
are also available by our method. Unfortunately, the
isolation of compound 6 (entry 5) was not as straight-
forward as for other compounds in Table 2. The isola-
tion of pure material required flash column chromato-
graphy of the crude reaction product. This also made
recycling of the ionic liquid difficult. Normally the ionic
liquid solvent [bmim][BF4] can be recovered in >90%
Acknowledgements
We thank Professor Kenneth Seddon and Dr. Martyn
Earle for scientific advice. Financial support to U.
Hakala from Emil Aaltonen foundation and Finnish
Academy (210633) is gratefully acknowledged.
References and notes
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A key starting material for the phytoestrogen glycitein,
2,4,40-trihydroxy-5-methoxydeoxybenzoin 8, has been
previously prepared using either the Hoesch15 or FC
reaction.16 In the latter case, the reaction of 4-methoxy-
resorcinol and 4-hydroxyphenyl acetic acid with
BF3ÆOEt2 as solvent and catalyst was reported to give
8 as a ‘dark yellow oil’, in 77% yield. This contrasts with
the present synthesis where an 88% yield of 8 was
obtained as a crystalline compound.17
2. Fokialakis, N.; Lambrinidis, G.; Mitsiou, D. J.; Skaltso-
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In summary, we have developed an expedient synthesis,
involving microwave irradiation in combination with an
ionic liquid/acidic additive system, of several poly-
hydroxydeoxybenzoins and arylpropanones, circum-
venting any protection/deprotection sequences, the use
of volatile organic compounds and with minimum
purification to yield the title compounds. Other green
chemistry considerations satisfied in our synthesis are
very short reaction times and moderate temperatures,
thus requiring much lower energy input, and the ready
recyclability of the reaction solvent.
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U. Hakala, K. Wa¨ha¨la¨ / Tetrahedron Letters 47 (2006) 8375–8378
9. Hardacre, C.; Katdare, S. P.; Milroy, D.; Nancarrow, P.;
by the addition of water. Any remaining ionic liquid was
washed off with dichloromethane. The product could also
be extracted into ether. In the [bmim][BF4] medium, the
reaction mixture was poured into water. The product was
then extracted with ethyl acetate. In the case of [bmim]Cl–
InCl3, the reaction mixture was poured into water and the
product was collected by filtration, under vacuum. All
reactions were carried out in open vessels, in a CEM
DiscoverÒ microwave reactor, with continuous cooling.
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13. In a typical reaction, resorcinol (1.2 mmol) and 4-
hydroxyphenylacetic acid (1 mmol) were dissolved in ionic
liquid and the mixture was dried under high vacuum after
which the catalyst was added. In the case of the chloro-
indate(III) ionic liquid, the reaction medium was prepared
in situ followed by the addition of the starting materials.
In the [bmim][NTf2] medium, the product was precipitated
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17. Melting point = 157 °C (recrystallised from aqueous
methanol).