New convenient synthesis of homoisoflavanones and (±)-di-O- methyldihydroeucomin

Article abstract of DOI:10.1081/SCC-200049789

Upon reaction of 1-(2-hydroxyphenyl)-3-phenylpropane-1-ones (2′-hydroxydihydrochalcones) with dimethylaminodimethoxymethane in boiling toluene, the corresponding 3-benzylchromones are obtained in excellent yields. These latter lead to 3-benzylchroman-4-on

Full text of DOI:10.1081/SCC-200049789

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New Convenient Synthesis
of Homoisoflavanones and
(±)‐Di‐O‐methyldihydroeucomin
B. Serge Kirkiacharian a & Michel Gomis a
a Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie de Paris‐Sud,
Chatenay, Malabry Cedex, France
Published online: 12 Apr 2011.
To cite this article: B. Serge Kirkiacharian & Michel Gomis (2005) New Convenient Synthesis of
Homoisoflavanones and (±)‐Di‐O‐methyldihydroeucomin, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:4, 563-569, DOI: 10.1081/SCC-200049789
To link to this article: http://dx.doi.org/10.1081/SCC-200049789
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Synthetic Communicationsw, 35: 563–569, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200049789
New Convenient Synthesis of
Homoisoflavanones and
(+)-Di-O-methyldihydroeucomin
B. Serge Kirkiacharian and Michel Gomis
´ ´
Laboratoire de Chimie Therapeutique, Faculte de Pharmacie
de Paris-Sud, Chatenay, Malabry Cedex, France
Abstract: Upon reaction of 1-(2-hydroxyphenyl)-3-phenylpropane-1-ones (20-hydroxy-
dihydrochalcones) with dimethylaminodimethoxymethane in boiling toluene, the
corresponding 3-benzylchromones are obtained in excellent yields. These latter lead
to 3-benzylchroman-4-ones (homoisoflavanones) by catalytic hydrogenetion. These
reactions were applied to the synthesis of (+)-3-benzylchroman-4-one and (+)-3-
(4-methoxybenzyl)-5,7-dimethoxychroman-4-one, (+)-di-O-methyldihydroeucomin.
Keywords: 3-Benzylchromones, homoisoflavanones, (+)-di-O-methyldihydroeucomin
INTRODUCTION
Homoisoflavonoids were isolated from Eucomis species: E. bicolor, E. autumna-
lis, E. punctata[1–5] and Ophiopogonis japonicus[6,7] belonging to the Liliaceae
family. The interest in this field continued with the isolation of novel derivatives
presenting various hydroxy(methoxy) substitution patterns.[8–10]
With the exception of Brazilin, Hematoxylin, and Scillascillins, the
homoisoflavanones constitute a homogenous group of naturally occurring
oxygen heterocyclic compounds and correspond to the biogenetically and
structurally related 3-benzylidenechroman-4-ones 1, 3-benzylchromones 2,
Received in the UK 19 August 2004
Address correspondence to B. Serge Kirkiacharian, Laboratoire de Chimie
´ ´
Therapeutique, Faculte de Pharmacie de Paris-Sud, 5, Rue J.B Clement, 92296
Chatenay, Malabry Cedex, France. E-mail: serge.kirkiacharian@cep.u-psud.fr

564
B. S. Kirkiacharian and M. Gomis
3-benzylchroman-4-ones 3a and 3-benzyl-3-hydroxy-chroman-4-ones 3b
(Fig. 1).[11]
Besides their phytochemical importance and as for the case of flavo-
noids, these derivatives display various biological properties. For instance,
3-benzylidene-chroman-4-ones, inhibit the growth, the sporogenesis and the
enzymes involved in the infection mechanism of Phytophtora parasitica[12]
and present antifungal activity.[13] Some substituted 3-benzylidene-
chroman-4-one display anti-inflammatory, analgesic, platelet anti-aggregat-
ing,[14] and hypocholesterolemic activites.[15] On the other hand, various
3-benzylchromones possess angioprotective, antiallergic, antihistaminic prop-
erties[16] and some natural derivatives display antimutagenic,[17] phosphodi-
esterase isoenzyme-inhibiting[18] and antiviral properties.[19,20]
During the course of a research program in connection with the preparation
of potential therapeutical agents, we had the requirement of large amounts of
3-benzyl-chromones. An extensive survey of the literature indicated that
3-benzyl-chromones may be obtained by the following procedures:
From 3-benzylidenchroman-4-ones by the isomerisation of their
exocyclic double bond into the pyrone ring, under the influence of
potassium tert-butyrate,[4] rhodium trichloride[21] or Raney nickel.[22] These
reactions lead generally to low yields and/or to mixtures.
By cyclization of conveniently substituted 1,3-diphenylpropane-1-ones
(20-hydroxydihydrochalcones) using ethylformate and sodium[23,16] or a
mixture of dimethylformamide, boron trifluoride and methanesulfonyl
chloride.[24] Although these methods lead to the expected derivatives, they
did not prove to be satisfactory for our needs of large-scale preparations.
In the case of 3-benzylchroman-4-ones, their preparation is limited by the
availability of the starting 3-benzylchromones. These latter are obtained with
low yields by direct cyclization of 20-hydroxydihydrochalcones with paraformal-
dehyde in basic media,[25] by hydroboration followed by chromic acid oxidation
of 3-benzyl-4-hydroxy-coumarins[26] or 3-benzylidene-chroman-4-ones.[27]
The availability of new convenient routes for the synthesis of these
derivatives would thus be interesting. Therefore, we investigated the elegant
chromone synthesis described by Fohlisch, in which a suitable 20-hydroxy-
acetophenone is condensed with dimethylaminodimethoxymethane to
form the corresponding enaminoketone, which is cyclized further to the
Figure 1. Reference compounds.

Homoisoflavanones and (+)-Di-O-methyldihydroeucomin
565
corresponding chromone in acidic media.[28] This method was applied further
to the preparation of isoflavones from 20-hydroxydeoxybenzoins.[29]
RESULTS
Our method follows the same design as these chromone preparations and results
from the condensation of suitable 1,3-diphenyl-propane-1-ones.[16] (20-hydroxy-
dihydrochalcones) with dimethylaminodimethoxymethane, a one-carbon unit
molecule. However, in our experiments, when the reaction was performed
with the various substituted derivatives 4a-g in boiling toluene, the expected
enaminoketones were not isolated and the unexpected 3-benzyl-chromones
5a-g were obtained directly in excellent yields (Scheme 1).
Table 1 shows the physicochemical data related to the prepared 3-benzyl-
chromones 5a-g. Their structure was established by elemental analysis, infrared
(v C ¼ 0: 1640cm 2 1), 1H and 13C NMR spectroscopy,[30] melting point and
mixed melting point with our previously prepared reference samples.[16]
The synthesis of 3-benzylchroman-4-ones was achieved in the case of (+)-
3-benzylchroman-4-one 6a and (+)-3-(4-methoxybenzyl)-5,7-dimethoxychro-
´
man-4-one, (+)-di-O-methyldihydroeucomin 6f, via the catalytic hydrogen-
ation of the corresponding 3-benzylchromones 5a and 5f (Scheme 2). The
structure of these derivatives was confirmed by elemental analysis, infrared,
melting point, and mixed melting point with reference samples.[4,25–27] The
overall yields of the homoisoflavanones prepared by these routes are higher
than those obtained with the previously described procedures.
In conclusion, this study indicates that it is now possible to prepare con-
veniently the 3-benzylchromones and the 3-benzylchroman-4-ones (homoiso-
flavanones) in excellent yields.
EXPERIMENTAL
Melting points are uncorrected. IR spectra were recorded on a Perkin-Elmer
1
177 spectrophotometer and H NMR spectra on a Varian T 60 spectrometer.
Glass equipment was dried at 1008C in an oven prior to use.
General Procedure for Compounds 5a–g
3-(3,4-Dimethoxybenzyl)chromone 5e
In a dry round-bottom flask, equipped with a magnetic stirring bar and a reflux
condenser topped with a calcium chloride drying tube, 1-(2-hydroxyphenyl)-
3-(3,4-dimethoxy-phenyl)propane-1-one 4e (20-hydroxy-3,4-dimethoxydihy-
drochalcone) (2.86 g, 10mmoles), dimethylaminodimethoxymethane (1.45 g,

Scheme 1. Synthesis of 3-benzylchromones.

Homoisoflavanones and (+)-Di-O-methyldihydroeucomin
Table 1. Physico-chemical data of 3-benzylchromones
567
Molecular
formula
Reaction
time
Yield
(%)a
m.p.8(C)
Litt.
m.p.8(C)
Product
(ethanol)b
5a
5b
5c
5d
5e
5f
C16H12O6
C17H14O3
C17H14O3
C17H12O4
C18H16O4
C19H18O5
C16H11O2Cl
5 h
5 h
5 h
5 h
6 h
6 h
6 h
94
95
97
92
91
95
94
109–110
130
100
110[16,23]
131[16]
101[16]
104[16]
115[16]
114[16]
140[16]
102–104
114
113
5g
140
aAll yields in isolated products.
bm.p. (uncorrected); mixed m.p. with reference samples not depressed.
12mmoles), and dry toluene (150ml) were refluxed during 5 h (the progress of
the reaction is monitored by tlc). When all the starting products have reacted, the
solvent is evaporated to give 2.87 g (97%) of pure 3-(3,4-dimethoxy-
benzylchromone 5e m.p. 102–1038C (ethanol).
Preparation of 3-Benzylchromones 5a–d and 5f–g
All reactions are performed from the corresponding 20-hydroxydihydrochal-
cones 4a–d and 4f–g according to the same procedure.
Products, yields and physico-chemical data are reported in Table 1.
General Procedure for Compounds 6a, 6f
(+)-3-(4-Methoxybenzyl)-5,7-dimethoxychroman-4-one: (+)-di-O-
´
methyldihydroeucomin 6f
A solution of 5,7-dimethoxy-3-(4-methoxybenzyl)-chromone 5f (326 mg,
1 mmol) in THF (50 mL) containing a pinch of 10% PD/C catalyst, is
Scheme 2. Synthesis of 3-benzylchroman-4-ones.

568
B. S. Kirkiacharian and M. Gomis
hydrogenated (1 atm) at r.t. until hydrogen (27 mL,1.2 mmol) was absorbed.
The reaction mixture is filtered and the solvent evaporated. The residue is
purified by column chromatography over silica gel (eluent: ethyl acetate-
petroleum ether 3–2). The crude product was recrystallized from petroleum
´
ether to give pure (+)-di-O-methyldihydroeucomin 6f, mp 838C; Litt.
82–848C.[4] Yield 259 mg (79%).
This compound has the same IR spectrum as a reference sample and its
mixed melting point with the reference sample is not depressed.[4]
(+) 3-Benzylchroman-4-one 6a
The synthesis of this compound was achieved with the same procedure, via the
catalytic hydrogenation of the 3-benzylchromone 5a. m.p. 638C; Litt.
62–648C;[26] yield 73%. This compound has the same IR spectrum as a
reference sample, and its mixed melting point with the reference sample, is
not depressed.
ACKNOWLEDGMENTS
We acknowledge our gratitude to Professor Ch. Tamm for the gift of a
reference sample of (+)-di-O-methyldihydroeucomin.
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