Synthesis of isoflavones via base catalysed condensation reaction of deoxybenzoin

Article abstract of DOI:10.3184/030823408X382135

Base catalysed condensation reaction of o-hydroxyl-α- phenylacetophenones with formyl reagents affords various substituted isoflavones. Many bases were tested in the condensation reaction and DMAP was found to be the most effective catalysis.

Full text of DOI:10.3184/030823408X382135

JOURNAL OF CHEMICAL RESEARCH 2008
DECEMBER, 683-685
RESEARCH PAPER 683
Synthesis of isoflavones via base catalysed condensation reaction of
deoxybenzoin
Wanmei Li*, Fangming Liu and Pengfei Zhang
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, P.R. China
Key Lab of Organosilicon Chemistry and Material Technology, Ministry of Education, Hangzhou Normal University, Hangzhou,
310012, P.R. China
Base catalysed condensation reaction of o-hydroxyl-a-phenylacetophenones
with formyl reagents affords various
substituted isoflavones. Many bases were tested in the condensation reaction and DMAP was found to be the most
effective catalysis.
Keywords: isoflavones, base, condensation reaction, formyl reagents
Isoflavones are widely distributed in nature and exert a variety
of biological effects on mammalian systems 1 that might be
exploitable in medicine.2-6
~Ph
~Ph
Formyl
llA OH
llA,o,)
Cat. I heat
1a
2a
Scheme
1
Formyl reagents to provide the additional carbon atom were
tested in the model cyclisation of a-phenyl-o-hydroxy-
acetophenone (Scheme 1, la). Many common inorganic and
organic bases were also investigated. The results are listed in
Table 1.
isoflavone
The two most popular synthetic pathways to isoflavones are
the deoxybenzoin (2-hydroxyphenylbenzyl ketones)7-11 and
the cha1coneI2-16routes. The beauty of the deoxybenzoin
route is the simplicity of the reaction as there is no need for
the protection of phenolic OH-groups. In the deoxybenzoin
route, cyclisation is the key step, which can be carried
out in many ways. The additional carbon atom needed for
the ring formation can be introduced by treatment with
one of the following combinations of reagents:- BF3Et20/
DMF/MeS02Cl,7,9 BF3Et20/DMF/PCI5,1O,11 HC02Et/Na.17
However, these methods often suffer from drawbacks such as
low yields, harsh reaction conditions, lengthy reaction times,
and the use of toxic reagents. The development of efficient
methods for the synthesis of isoflavones is of interest. Herein,
we report an effective combination of reagents for the
synthesis ofisoflavones from deoxybenzoin via a condensation
reaction.
The results in Table 1 show that inorganic bases including
NaOAc, NaOH, K2C03 (entries 8, 9 and 10) showed poor
reactivity. Many organic bases, especially DMAP (entries 13
and 14), exhibited good to excellent catalysis with up to 96%
yield. IfDMF was used as the formyl reagent without any other
basic catalyst (entry 3),38% yield of2a was obtained, while
only trace of 2a could be obtained under the same reaction
condition when triethyl orthoformate was used (entry 4).
This may be due to a base from DMF. The condensation
reaction of la with formyl reagent in the presence of DMAP
was also performed in several organic solvents such as
toluene, chloroform, THF, ethanol, acetonitrile, but the
yields were not comparable to those in 1 ml formyl reagent.
We also performed the reaction under solvent-free condition,
i.e. 2 mmolla and 3 mmol triethyl orthoformate was heated
Table
Entry
1
Cyclisation of a-phenyl-o-hydroxyacetophenone
under different conditions"
Catalyst (equiv.)b Temperature;oC
Yield/%C
Formyl
Time/h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
DMF
DMF
DMF
Et3N (0.1)
DMAP (0.1)
80
100
~
80
80
100
100
100
100
100
100
100
100
100
50
6
4
6
6
6
6
6
6
6
6
6
6
4
4
10
4
71
92
38
<5
74
82
85
36
41
44
76
86
96
95
81
90
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HC(OEtb
HCOOEt
HCONH2
Et3N (0.1)
Pyridine (0.1)
3-Methyl pyridine (0.1)
NaOAc (1.0)
NaOH (1.0)
K2C03 (1.0)
Morpholine (0.1)
DABCO (0.1)
DMAP (0.1)
DMAP (0.02)
DMAP (0.02)
DMAP (0.02)
100
"2.0 mmol1a and 1 ml formyl reagent were used.
bBased on 1a, DABCO: 1,4-diazabicyclo[2.2.2]octane;
cBased on 1a.
DMAP: 4-dimethylaminopyridine.
* Correspondent. E-mail: liwanmei206@163.com

684 JOURNAL OF CHEMICAL RESEARCH 2008
HC(OEth
2 mol% DMAP
100°C, 4 h
2
Scheme
2
Preparation of isoflavones.
the acetal 4 was obtained when the reaction was carried out
with triethyl orthoformate in the presence of gaseous HCI or
para-toluene sulfonic acid (p-TSA). A plausible mechanism was
postulated in Scheme 5. The Knoevenagel reaction proceeded
firstly in the presence of DMAP to form the unsaturated
ketone B, followed by a Michael addition and elimination of
ethanol to obtain the desired product 2a.
at 100°C for 4 h in the presence of catalytic amount ofDMAP
(2 mol%), but the yield of 2a was only about 50%. Due to
the poor mixing under the given condition, the substrates did
not react well. If excess triethyl orthoformate was added to
improve mixing, the yield was increased obviously.
With these results in hand, the reaction was extended
to many o-hydroxyl-a-phenylacetophenone
derivatives.
In summary, DMAP is an effective catalyst for the synthesis
of isoflavones from o-hydroxyl-a-phenylacetophenone
The condensation reaction was carried out using 0.02 equiv.
of DMAP as the catalyst in I ml of triethyl orthoformate
(Scheme 2). The results were shown in Table 2.
derivatives via
a condensation reaction with triethyl
All the substrates were satisfactorily converted to the
desired product in high yield. The aromatic substituents did
not obviously affect the yield. In addition, methylated product
could be easily transformed to hydroxy product in good yield
using demethylation reagent such us BBr3 (Scheme 3).
In order to investigate the reaction mechanism, a test
reaction (Scheme 4) was carried out To our surprise, no
reaction occurred when o-hydroxylbenzophenone was treated
with triethyl orthoformate using DMAP. But high yield
orthoformate. The advantages of above method include good
selectivity, high yields, catalytic reaction, short reaction time
and simple process. Isoflavones are useful compounds for its
potential bioactivity and pharmacological activity.
Experimental
Melting points were uncorrected. IR spectra were recorded using
KEr pellets on a Nicolet NEXUS-470-FT-IR
instrument. The NMR
spectra were measured with a Bruker-400 instrument using CDCl3
HO
MeO
3.0 equiv. BBr3
OMe
2e
2f
84%
Scheme
3
Demethylation
R6
of 2e.
Preparation of isoflavones in the presence of DMApa
Table
Entry
2
Yield/%b
R2
Rg
Product
R,
R3
R4
R5
R7
Rs
1
2
3
4
5
6
7
8
9
10
H
H
OH
H
H
H
H
H
H
H
H
H
OH
H
H
H
H
OMe
OH
H
OMe
OH
OMe
OH
OH
OH
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CI
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
2g
2h
2i
95
94
92
95
94
90
93
95
91
90
CI
OMe
OH
OMe
CI
H
OMe
H
OH
OH
OH
2j
a2 mmol1 and 1 ml triethyl orthoformate
bisolated yield based on 1.
were used.
DMAP
heat
No reaction
~Ph.
ceOEbEt
HC(OEth
llAOH
HClorp-TSA
heat
I ~
Ph
,,:;:; O-CH(OEt12
3
4
Scheme
4
Reaction of o-hydroxylbenzophenone
with triethyl orthoformate.

JOURNAL OF CHEMICAL RESEARCH 2008 685
( 0
0
APh_D_MA_p_rPh ~ 2a
~cillOEt
~O~OEt
B
c
Scheme
5
Possible route to the formation of 2a.
1605 em-I; IH NMR (DMSO-d6, 400 MHz): 8 = 12.78 (s, lH), 9.80
(s, lH), 8.39 (s, lH), 7.86 (d, lH, J = 1.6 Hz), 7.62-7.65 (m,2H),
6.44 (d, lH,J= 1.6 Hz), 6.31 (d, lH,J= 1.6 Hz); BC NMR (DMSO-
d6, 100 MHz): 8 = 94.0, 99.4, 105.3, 121.0, 129.0, 130.3, 130.9,
131.5, 131.6, 131.9, 155.2, 158.2, 163.0, 164.4, 179.8. MS (m/z)
325, 324, 323.
5,7-Dihydroxy-3'-methoxyisojlavone (2i): White solid; m.p. 301-
305°C (decomposed). [lit.25]. IR (KBr) vrnax: 3448, 3400, 1659,
1613 em-I; lH NMR (DMSO-~, 400 MHz): 8 = 13.08 (s, lH), 8.23
(s, lH), 7.34 (t, lH, J = 7.2 Hz), 7.18-7.21 (m, 2H), 6.95-6.97 (m,
lH,), 6.45 (d, lH,J= 1.6 Hz), 6.32 (d, lH,J= 1.6 Hz), 3.88 (s, 3H);
BC NMR (DMSO-d6, 100 MHz): 8 = 54.5,93.8,99.1, 105.3, 113.4,
114.9, 121.1, 123.1, 129.3, 132.4, 154.5, 158.2, 159.7, 163.0, 164.3,
180.3. MS (m/z) 285.
5,7-Dihydroxy-4'-methoxyisojfo.vone (2j): White solid; m.p. 207-
209°C. [lit.20:211-213°C]. IR (KBr) vrnax: 3438,3406, 1655, 1616
em-I; lH NMR (DMSO-~, 400 MHz): 8 = 12.88 (s, lH), 10.86
(s, lH), 8.38 (s, lH), 7.52 (d, 2H,J= 8.0 Hz), 7.00 (d, 2H,J= 8.0 Hz),
6.41 (d, lH, J = 1.6 Hz), 6.24 (d, lH, J = 1.6 Hz), 3.82 (s, 3H); BC
NMR (DMSO-d6, 100 MHz): 8 = 55.4, 94.3, 99.3,105.3,114.1,123.1,
or DMSO-d6 as the solvent with TMS as internal standard. Chemical
shifts (8) are reported in ppm and coupling constants J is given in
Hz. Mass spectra were measured with Broker Esquire-3000-plus
spectrometer. All spectral data of the products were identical to
authentic samples.
General procedure
To a solution of 1 (2 mmol) in 1 ml triethyl orthoformate, DMAP
(0.04 mm04 4.9 mg) were added. The reaction mixture was heated
to 100°C and stired for 4 h. After completion (monitored by TLC)
the reaction mixture was quenched with water (10 ml) and extracted
with CH2Cl2 (10 ml x 3). The organic phase was washed with brine
and dried over MgS04. After concentration in vacuum, the residue
was purified by column chromatography using petroleum ether-ethyl
acetate (8 : 1) as eluent to afford 2 (generally up to 90% yield).
Spectra data for products.-
Isojfo.vone (2a): White solid; m.p. 128.5-129.5°C. [lit.(18): 131-
132°C]. IR (KBr) vrnax: 3045, 1641, 1611 em-I; IH NMR (CDC13,
400 MHz): 8 = 7.35-7.48 (m, 5H), 7.57-7.60 (m, 2H), 7.68-7.74 (m,
lH), 8.01 (s, lH) 8.28-8.31 (m, lH); BC NMR (CDC13, 100 MHz):
8 = 118.1, 124.5, 125.1, 125.4, 126.4, 128.3, 128.5, 128.8, 131.7,
133.6, 153.2, 156.2, 176.3. MS (m/z) 223.
7-Methoxyisojfo.vone (2b): White solid; m.p. 157.5-159.0°C.
[lit. 19: 156-158°C]. IR (KBr) vrnax: 3041, 1651, 1608 em-I;
IH NMR (DMSO-d6, 400 MHz): 8 = 3.93 (s, 3H), 7.07 (dd, lH,
J = 8.8 Hz, 2.0 Hz), 7.16 (d, lH, J = 1.6 Hz), 7.39 (m, lH) 7.45 (t,
2H,J= 6.8 Hz, 7.2 Hz), 7.59 (d, 2H,J= 6.8 Hz), 8.05 (d, lH,J= 8.4
Hz), 8.48 (s, lH); BC NMR (DMSO-d6, 100 MHz): 8 = 55.1, 100.2,
109.7. 118.5, 125.3, 128.5, 128.7, 128.9, 129.1, 131.5, 152.3, 157.6,
164.1, 175.8. MS (m/z) 253.
5,7-Dihydroxyisojlavone (2c): White solid; m.p. 195.5-197.0°C.
[lit.2o: 198-201°C]. IR (KBr) vrnax: 3440, 3380, 1651, 1614 em-I;
IH NMR (DMSO-d6, 400 MHz): 8 = 6.31 (d, lH, J= 1.6 Hz), 6.45
(d, lH,J= 1.6 Hz, 2.0 Hz), 7.46-7.54 (m, 5H), 8.25 (s, lH), 9.77 (s,
lH), 13.05 (s, lH); BC NMR (DMSO-~, 100 MHz): 8 = 93.6, 99.0,
105.4, 123.1, 128.4, 129.2, 131.1, 154.3, 158.2, 163.1, 164.1, 180.6.
MS (m/z) 255.
123.5,130.2,152.9,158.1,159.8,162.2,164.0,180.6.
MS (m/z) 285.
We thank Hangzhou Normal University for financial support.
Received 10 September 2008; accepted 13 October 2008
Paper 08/0164 doi: 10.3184/030823408X382135
Published online: 10 December 2008
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(DMSO-d6, 400 MHz): 8 = 8.25 (s, lH), 7.98 (d, lH, J = 7.6 Hz),
7.36-7.39 (m, 2H), 6.92 (dd, lH, J = 1.6, 7.6 Hz), 6.85 (d, lH,
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6.88-6.91 (m, 3H), 4.02 (s, 3H), 3.98 (s, 3H); BC NMR (DMSO-d6,
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130.1, 145.4, 151.1, 152.4, 153.8, 159.0, 174.7. MS (m/z) 299.
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295-299°C (decomposed). [lit.25].IR (KBr) vrnax: 3538,3480, 1650,