A concise synthesis of polyhydroxydihydrochalcones and homoisoflavonoids

Article abstract of DOI:10.1016/j.tet.2005.10.059

A general and single step synthesis of polyhydroxydihydrochalcones from the readily available phenols and dihydrocinnamic acids using BF ₃·Et₂O is described. The method allows the synthesis of a wide range of compounds with multiple phenolic hydroxyls and other substituents. These dihydrochalcones are converted into homoisoflavonoids by DMF/PCl₅ and the methodology has been applied to the synthesis of naturally occurring phloretin and 5,7-dihydroxy-3-[(4-hydroxyphenyl)methyl]-4H- chromen-4-one. The antioxidant activity of dihydrochalcones and homoisoflavonoids was determined by superoxide free radical (NBT) and DPPH free radical scavenging methods. Polyhydroxydihydrochalcones 3c, 3f, 3g and homoisoflavonoids 4c, 4f, 4g displayed excellent antioxidant activity.

Full text of DOI:10.1016/j.tet.2005.10.059

Tetrahedron 62 (2006) 841–846
A concise synthesis of polyhydroxydihydrochalcones
and homoisoflavonoids
Vidavalur Siddaiah,a Chunduri Venkata Rao,a Somepalli Venkateswarlub
and Gottumukkala V. Subbarajub,
*
aDepartment of Chemistry, Sri Venkateswara University, Tirupati 517 502, India
bLaila Impex Research Centre, Unit 1, Phase III, Jawahar Autonagar, Vijayawada 520 007, India
Received 29 June 2005; revised 3 October 2005; accepted 20 October 2005
Available online 9 November 2005
Abstract—A general and single step synthesis of polyhydroxydihydrochalcones from the readily available phenols and dihydrocinnamic
acids using BF3$Et2O is described. The method allows the synthesis of a wide range of compounds with multiple phenolic hydroxyls and
other substituents. These dihydrochalcones are converted into homoisoflavonoids by DMF/PCl5 and the methodology has been applied to the
synthesis of naturally occurring phloretin and 5,7-dihydroxy-3-[(4-hydroxyphenyl)methyl]-4H-chromen-4-one. The antioxidant activity of
dihydrochalcones and homoisoflavonoids was determined by superoxide free radical (NBT) and DPPH free radical scavenging methods.
Polyhydroxydihydrochalcones 3c, 3f, 3g and homoisoflavonoids 4c, 4f, 4g displayed excellent antioxidant activity.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
DHCs. The homoisoflavonoids (3-benzylchromen-4-ones),
are naturally occurring compounds and are structurally
related to flavonoids,10 and display a wide spectrum of
biological activities.11–15 A few methods of synthesis have
been reported in the literature for homoisoflavonoids and
these were based on (i) the condensation of 4-chromanones
with arylaldehydes in methanol by passing HCl gas or by
using piperidine as a base16,17 followed by isomerisation of
the double bond using Pd/C at 250 8C, (ii) hydrogenation
of chalcones followed by one carbon extension using ethyl
formate/sodium18 or methanesulfonyl chloride/DMF.19
Both the methods have disadvantages; while the first
method has multiple steps, in the second method, the
phenolic hydroxyls have to be protected to get chalcones in
good yield. Our interest in the chemistry of the
flavonoids20 and an increasing demand for a short, and
efficient method prompted us to develop a simple and
general method for the synthesis of DHCs and homo-
isoflavonoids. The methodology has been applied to the
synthesis of phloretin,21 a naturally occurring DHC and
5,7-dihydroxy-3-[(4-hydroxyphenyl)-methyl]-4H-chromen-
4-one, a homoisoflavonoid from Ophiopogon jaburan.22
Moreover, to the best of our knowledge, there is no report
in the literature on the antioxidant activity of homo-
isoflavonoids. So we report in this paper, the details of
synthesis of DHCs, homoisoflavonoids and their anti-
oxidative activity results.
Naturally occurring polyphenolic compounds display wide
spectrum of biological activities. Polyphenolic flavonoids
have gained increasing importance in view of their strong
antioxidant activity and preventing role in free radical
mediated disorders such as cancer, Alzheimer’s,
Parkinson’s, and cardiovascular diseases.1 Dihydro-
chalcones (DHCs), the reduced form of chalcones, have
been known to occur widely in nature and are important
intermediates for many natural products and pharma-
ceutical drugs.1 DHCs have been reported to have various
biological activities2,3 and have received considerable
attention as food sweeteners (neohesperidin).4 Up to now,
DHCs were mostly synthesized through a Claisen–Schmidt
condensation5,6 to obtain chalcone, followed by reduction
to DHC or through the alkaline reduction of a correspon-
ding flavanone.7,8 Although widely used, the procedures
are not suitable for polyhydroxyDHCs, as these methods
require protection of all phenolic hydroxyls. Recently,
palladium mediated coupling of iodobenzenes and the enol
of acetophenone was reported9 as an alternative route to
Keywords: Dihydrochalcones; Homoisoflavonoids; Boron trifluoride
etherate; Antioxidant activity.
Corresponding author. Tel.: C91 866 2541303; fax: C91 866 2546216;
e-mail: subbarajugottumukkala@hotmail.com
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.059

842
V. Siddaiah et al. / Tetrahedron 62 (2006) 841–846
2. Results and discussion
chloride. The spectral data of synthetic 3h and 4h were
found to be identical with those of the corresponding natural
products.19
2.1. Synthesis
During the course of our investigations of new synthetic
routes to flavonoids, we have found that a Friedel-Crafts
reaction constitutes a novel and efficient approach to DHCs.
The method involves the preparation of DHCs in a single
step from phenols and dihydrocinnamic acids by Friedel-
Crafts acylation using boron trifluoride etherate, which
serves as the Lewis acid for the acylation and as solvent for
the reaction (Scheme 1). In this method, protection of the
phenolic hydroxyls is not necessary. In a typical experiment,
substituted phenol (1, 3 mmol) and dihydrocinnamic acid
(2, 3 mmol) was treated with boron trifluoride etherate at
80–90 8C for 90 min. After completion of the reaction
(monitored by TLC), it was poured into aqueous sodium
acetate and extracted with ethyl acetate to give DHCs (3).
The generality of the reaction was established with various
phenols and substituted dihydrocinnamic acids and in all
cases (Table 1, 7 examples) the reaction was completed
within 90 min. In the second step, the DHCs (3a–3g) were
treated with N,N0-dimethyl(chloromethylene)ammonium
chloride23 generated in situ from DMF and PCl5 for one
carbon extension to get homoisoflavonoids (4a–4g) in
78–88% yield (Table 1). In all cases the reaction was
complete in 2 h and the products were characterized by their
spectral data (IR, NMR and Mass). The methodology has
been applied to the synthesis of naturally occurring
phloretin,21 a DHC and 5,7-dihydroxy-3-[(4-hydroxy-
phenyl)methyl]-4H-chromen-4-one (4h), isolated from
Ophiopogon jaburan.22 Reaction of phloroglucinol and
4-hydroxydihydrocinnamic acid with BF3$Et2O gave
phloretin (3h), which was converted further into 4h (85%
yield) using N,N0-dimethyl(chloromethylene)ammonium
2.2. Antioxidant activity
We have determined the antioxidative activity of DHCs
(3a–3h) and homoisoflavonoids (4a–4h) by nitro blue
tetrazolium (NBT)24,25 and 1,1-diphenyl-2-picrylhydrazyl
(DPPH)26 free radical scavenging methods. The IC50 values
of these compounds are presented in Table 2. DHCs 3f
(IC50: 12.9 mM), 3g (IC50: 19.6 mM) and 3c (IC50: 30.2 mM)
and homoisoflavonoids 4f (IC50: 6.3 mM), 4g (IC50: 8.2 mM)
and 4c (IC50: 24.8 mM) having catechol moieties were the
most active compounds. Interestingly 3f, 3g and 3c and 4f,
4g and 4c showed several-fold more potent activity than
vitamin C (IC50: 852 mM), vitamin E (IC50: 726 mM), BHA
(IC50: 966 mM) and BHT (IC50: 381 mM). The same order
of activity was followed by DHCs 3a–3h and homo-
isoflavonoids 4a–4h with the DPPH method. Again 3c, 3f
and 3g and 4c, 4f and 4g showed good DPPH free radical
scavenging activity. The superior antioxidative activity of
these compounds lends further support to the fact that the
catechol system enhances the antioxidative activity.27
3. Conclusions
In conclusion, we have described a general, single step
method for the synthesis of polyhydroxydihydrochalcones
using phenols and dihydrocinamic acids with BF3$Et2O.
One carbon extension of these dihydrochalcones into
homoisoflavonoids by DMF/PCl5 was achieved in good
yields. The DHCs and homoisoflavonoids were evaluated
for their antioxidative potential by two commonly used
R1
R4
R1
R2
OH
O
R6
R5
R2
OH
R5
R6
COOH
(i)
+
R3
R4
R3
2
3
1
R1
8
O1
R6
4'
5'
R2
6'
2
(ii)
6
4
R5
2'
9
R3
O
R4
4
Scheme 1. Reagents and conditions: (i) BF3$Et2O, 80–90 8C, 90 min, 30–71% (ii) BF3$Et2O, DMF/PCl5, rt, 2 h, 78–88%.
Table 1. Dihydrochalcones 3 and homoisoflavonoids 4
S.no.
Entry
R1
R2
R3
R4
R5
R6
3 Yield (%)a 4 Yield (%)a
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
H
H
H
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
H
H
H
H
OH
H
H
H
H
OCH3
H
H
H
H
OH
OCH3
H
H
H
H
OH
OCH3
OH
OCH3
OCH3
OH
62
71
55
68
61
58
65
30
85
88
82
87
78
80
81
85
H
OH
OH
H
g
h
OCH3
OH
H
a Unoptimized isolated yields.

V. Siddaiah et al. / Tetrahedron 62 (2006) 841–846
843
(1H, d, JZ8.8 Hz, H-600), 7.04 (2H, d, JZ8.3 Hz, H-20,60),
6.65 (2H, d, JZ8.3 Hz, H-30,50), 6.35 (1H, dd, JZ8.8,
2.4 Hz, H-500), 6.24 (1H, d, JZ2.4 Hz, H-300), 3.20 (2H, t,
JZ7.6 Hz, H-3), 2.81 (2H, t, JZ7.6 Hz, H-2); 13C NMR
(DMSO-d6): d 203.9, 164.7, 164.3, 155.5, 133.0, 131.0,
129.3, 115.1, 112.6, 108.2, 102.4, 39.1, 29.1; MS (ESI,
negative ion mode): m/z 257 (MKH)K. Analysis found: C,
69.68; H, 5.52%. Calcd for C15H14O4: C, 69.76; H, 5.46%.
Table 2. Antioxidant activity of homoisoflavonoids
Compound NBT superoxide scavenging DPPH free radical scaven-
no.
activity (IC50 in mM)
ging activity (IC50 in mM)
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
O100
O100
30.2
O100
O100
12.9
19.6
16.6
O100
O100
24.8
O100
O100
7.8
O100
O100
11.3
14.9
95
O100
O100
13.4
4.2.2. 1-(2,4-Dihydroxyphenyl)-3-(4-methoxyphenyl)-
propan-1-one (3b). Light brown powder (580 mg, 71%),
mp 58–60 8C; IR (KBr): 3456, 3105, 1629, 1225, 1131,
1
1029, 990 cmK1; H NMR (DMSO-d6): d 12.60 (1H, s,
4d
4e
4f
4g
O100
O100
6.3
8.2
17.6
852
726
O100
O100
19.0
19.6
O100
25.1
O100
34.0
22.5
Ar-OH), 10.61 (1H, s, Ar-OH), 7.79 0(1H, d, JZ8.8 Hz,
H-600), 7.160(2H, d, JZ8.3 Hz, H-20,6 ), 6.82 (2H, d, JZ
8.3 Hz, H-3 ,50), 6.34 (1H, dd, JZ8.8, 2.0 Hz, H-500), 6.23
(1H, d, JZ2.0 Hz, H-300), 3.69 (3H, s, Ar-OCH3), 3.22 (2H,
t, JZ7.5 Hz, H-3), 2.84 (2H, t, JZ7.5 Hz, H-2); 13C NMR
(DMSO-d6): d 203.7, 164.8, 164.3, 157.6, 132.9, 129.4,
114.2, 113.7, 112.6, 108.2, 102.5, 55.0, 40.1, 29.0; MS (ESI,
negative ion mode): m/z 271 (MKH)K. Analysis found: C,
70.52; H, 5.97%. Calcd for C16H16O4: C, 70.58; H, 5.92%.
4h
Vitamin C
Vitamin E
BHA
BHT
966
381
BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; NBT,
nitro blue tetrazolium; DPPH, 1,1-diphenyl-2-picrylhydrazyl. The lower
the IC50 values, the higher is the antioxidant activity.
4.2.3. 1-(2,4-Dihydroxyphenyl)-3-(3,4-dihydroxyphenyl)-
propan-1-one (3c). Colorless powder (450 mg, 55%), mp
108–110 8C; IR (KBr): 3339, 1638, 1605, 1286, 1222,
1200, 1174, 1141, 968 cmK1; 1H NMR (DMSO-d6): d 12.63
(1H, s, Ar-OH), 8.72 (1H, s, Ar-OH), 8.56 (1H, s, Ar-OH),
8.29 (1H, s, Ar-OH),0 70.77 (1H, d, JZ8.8 Hz, H-600),
7.10–7.20 (2H, m, H-2 ,5 ), 6.47 (1H, dd, JZ7.8, 1.5 Hz,
H-60), 6.34 (1H, dd, JZ8.8, 2.0 Hz, H-500), 6.23 (1H, d, JZ
2.0 Hz, H-300), 3.16 (2H, t, JZ7.6 Hz, H-3), 2.74 (2H, t, JZ
7.6 Hz, H-2); 13C NMR (DMSO-d6): d 205.0, 165.9, 165.4,
146.1, 144.5, 134.1, 133.0, 120.1, 117.0, 116.6, 113.7,
109.3, 103.6, 40.4, 30.4; MS (ESI, negative ion mode): m/z
273 (MKH)K. Analysis found: C, 65.64; H, 5.18%. Calcd
for C15H14O5: C, 65.69; H, 5.15%.
methods, the superoxide and DPPH free radical scavenging
methods. DHCs 3c, 3f and 3g and homoisoflavonoids 4c, 4f
and 4g were potent antioxidants.
4. Experimental
4.1. General
Melting points were recorded on a Mel-Temp melting point
apparatus, in open capillaries and are uncorrected. IR
spectra were recorded on a Perkin-Elmer BX1 FTIR
1
Spectrophotometer and H NMR (400 MHz), 13C NMR-
DEPT (100 MHz) spectra were recorded on a Bruker AMX
400 MHz NMR spectrometer using TMS as internal
standard and the values for chemical shifts (d) being given
in ppm and coupling constants (J) in Hertz (Hz). Mass
spectra were recorded on an Agilent 1100 LC/MSD. Acme
silica gel G and silica gel (100–200 mesh) were used for
analytical TLC and column chromatography, respectively.
4.2.4. 1-(2,4-Dihydroxyphenyl)-3-(3,4-dimethoxyphenyl)-
propan-1-one (3d). Light brown powder (615 mg, 68%),
mp 128–130 8C; IR (KBr): 3371, 1631, 1257, 1235, 1209,
1137, 1026, 991 cmK1 1H NMR (DMSO-d6): d 12.64
;
(1H, s, Ar-OH), 10.63 (1H, s, Ar-OH), 7.82 (1H, d,
JZ8.8 Hz, H-600), 6.88 (1H, d, JZ1.8 Hz, H-20), 6.83
(1H, d, JZ8.0 Hz, H-50), 6.76 (1H, dd0,0 JZ8.0, 1.8 Hz, H-
60), 6.37 (1H, dd, JZ8.8, 2.1 Hz, H-5 ), 6.26 (1H, d, JZ
2.1 Hz, H-300), 3.73 (3H, s, Ar-OCH3), 3.70 (3H, s, Ar-
OCH3), 3.25 (2H, t, JZ7.6 Hz, H-3), 2.86 (2H, t, JZ7.6 Hz,
H-2); 13C NMR (DMSO-d6): d 203.8, 164.8, 164.3, 148.7,
147.2, 133.5, 133.0, 120.2, 112.6, 112.4, 111.9, 108.2,
102.5, 55.5, 55.4, 39.2, 29.5; MS (ESI, negative ion mode):
m/z 301 (MKH)K. Analysis found: C, 67.52; H, 6.04%.
Calcd for C17H18O5: C, 67.54; H, 6.00%.
4.2. General procedure for dihydrochalcones (3)
A mixture of phenol (1, 3 mmol), 3-phenylpropanoic acid
(2, 3 mmol) and BF3$Et2O (1.94 mL, 15.3 mmol) was
stirred at 80–90 8C for 90 min under N2. The reaction
mixture was poured into 10% aqueous NaOAc solution
(100 mL) and allowed to stand for 4 h and the solution was
extracted with EtOAc (3!100 mL). The combined EtOAc
layer was washed with water (20 mL), brine (20 mL) and
dried over Na2SO4. The residue obtained after evaporation
of the solvent was chromatographed over silica gel column
using hexane–EtOAc mixtures as eluent to give 3a–h.
4.2.5. 1-(2,4-Dihydroxyphenyl)-3-(2,4-dimethoxyphenyl)-
propan-1-one (3e). Colorless powder (555 mg, 61%), mp
110–112 8C; IR (Neat): 3347, 1626, 1290, 1208, 1153,
1
1037, 990 cmK1; H NMR (DMSO-d6): d 12.72 (1H, s,
4.2.1. 1-(2,4-Dihydroxyphenyl)-3-(4-hydroxyphenyl)-
propan-1-one (3a). Light brown powder (480 mg, 62%),
mp 140–142 8C; IR (KBr): 3456, 3270, 1626, 1214, 1165,
Ar-OH), 9.99 (1H, s, Ar-OH), 7.6000 (1H, d, JZ8.5 Hz,
H-6000), 07.0000(1H, d, JZ8.5 Hz, H-5 ), 6.20–6.40 (4H, m,
H-3 ,5 ,60,3 ), 3.81 (3H, s, Ar-OCH3), 3.78 (3H, s,
Ar-OCH3), 3.10 (2H, t, JZ7.5 Hz, H-3), 2.90 (2H, t,
JZ7.5 Hz, H-2); 13C NMR (DMSO-d6): d 204.2, 164.8,
1
1134, 987 cmK1; H NMR (DMSO-d6): d 12.63 (1H, s,
Ar-OH), 11.69 (1H, s, Ar-OH), 10.60 (1H, s, Ar-OH), 7.79

844
V. Siddaiah et al. / Tetrahedron 62 (2006) 841–846
164.4, 159.2, 158.0, 132.9, 130.0, 120.8, 112.5, 108.2,
104.3, 102.5, 98.3, 55.5, 55.3, 38.0, 24.8; MS (ESI, negative
ion mode): m/z 301 (MKH)K. Analysis found: C, 67.51; H,
6.05%. Calcd for C17H18O5: C, 67.54; H, 6.00%.
4.3.1. 7-Hydroxy-3-[(4-hydroxyphenyl)methyl]-4H-
chromen-4-one (4a). Colorless powder (680 mg, 85%),
mp 212–214 8C; IR (KBr): 3430, 1628, 1600, 1267, 1244,
1176, 1140, 1099, 960 cmK1; 1H NMR (DMSO-d6): d 10.73
(2H, br s, Ar-OH), 8.04 (1H, s, H-2),07.86 (1H, d, JZ8.8 Hz,
H-5), 7.06 (2H, d, JZ8.3 Hz, H-20,6 ), 6.88 (1H, dd, JZ8.8,
2.2 Hz, H-6), 6.79 (1H, d, JZ2.2 Hz, H-8), 6.65 (1H, d, JZ
8.3 Hz, H-30,50), 3.53 (2H, s, H-9); 13C NMR (CDCl3C
DMSO-d6): d 176.3, 162.2, 157.8, 155.4, 152.2, 129.4,
128.9, 126.6, 123.8, 116.3, 115.1, 114.6, 102.0, 30.2; MS
(ESI, negative ion mode): m/z 267 (MKH)K. Analysis
found: C, 71.59; H, 4.55%. Calcd for C16H12O4: C, 71.64;
H, 4.51%.
4.2.6. 1-(2,3,4-Trihydroxyphenyl)-3-(4-hydroxyphenyl)-
propan-1-one (3f). Pale green powder (475 mg, 58%), mp
158–160 8C; IR (KBr): 3440, 3246, 1633, 1243, 1213, 1118,
1044, 1004, 899 cmK1; 1H NMR (DMSO-d6): d 12.63 (1H,
s, Ar-OH), 10.06 (1H, s, Ar-OH), 9.15 (1H, s, Ar-OH), 8.59
(1H, s, Ar-OH),0 7.034 (1H, d, JZ8.8 Hz, H-600), 7.04 0(2H, d,
JZ8.3 Hz, H-2 ,6 ), 6.66 (2H, d, JZ8.3 Hz, H-30,5 ), 6.38
(1H, d, JZ8.8 Hz, H-500), 3.20 (2H, t, JZ7.5 Hz, H-3), 2.82
(2H, t, JZ7.5 Hz, H-2); 13C NMR (DMSO-d6): d 204.9,
155.7, 152.6, 152.4, 132.5, 131.2, 129.4, 122.6, 115.2,
113.0, 107.9, 39.0, 29.4; MS (ESI, negative ion mode): m/z
273 (MKH)K. Analysis found: C, 65.66; H, 5.20%. Calcd
for C15H14O5: C, 65.69; H, 5.15%.
4.3.2. 7-Hydroxy-3-[(4-methoxyphenyl)methyl]-4H-
chromen-4-one (4b). Light brown powder (740 mg,
88%), mp 162–164 8C; IR (KBr): 3433, 1631, 1248, 1161,
1132, 1096, 1034 cmK1; 1H NMR (DMSO-d6): d 10.55 (1H,
s, Ar-OH), 7.96 (1H, s, H-2), 7.87 (1H, d, JZ8.8 Hz, H-5),
7.19 (2H, d, JZ8.3 Hz, H-20,60), 6.86 (1H, dd, JZ8.8,
2.0 Hz, H-6), 6.80 (2H, d, JZ8.3 Hz, H-30,50), 6.71 (1H, d,
JZ2.0 Hz, H-8), 3.72 (3H, s, Ar-OCH3), 3.61 (2H, s, H-9);
13C NMR (CDCl3CDMSO-d6): d 176.2, 162.2, 157.8,
157.6, 152.1, 130.6, 129.4, 126.6, 123.5, 116.3, 114.6,
113.4, 102.0, 54.7, 30.2; MS (ESI, negative ion mode): m/z
281 (MKH)K. Analysis found: C, 72.29; H, 5.04%. Calcd
for C17H14O4: C, 72.33; H, 5.00%.
4.2.7. 1-(2,3,4-Trihydroxyphenyl)-3-(4-methoxyphenyl)-
propan-1-one (3g). Light brown oil (560 mg, 65%), IR
(Neat): 3396, 2928, 1632, 1244, 1178, 1114, 1033, 999 cmK1
;
1H NMR (DMSO-d6): d 12.60 (1H, s, Ar-OH), 10.08 (1H, s,
Ar-OH), 8.61 (1H, s, Ar-OH),07.33 (1H, d, JZ8.8 Hz, H-600),
7.16 (2H, d, JZ7.8 Hz, H-2 ,60), 6.81 (2H, d, JZ7.8 Hz,
H-30,50), 6.38 (1H, d, JZ8.8 Hz, H-500), 3.69 (3H, s,
Ar-OCH3), 3.20 (2H, t, JZ7.5 Hz, H-3), 2.85 (2H, t, JZ
7.5 Hz, H-2); 13C NMR (DMSO-d6): d 204.8, 157.8, 152.7,
152.6, 133.1, 132.6, 129.6, 122.6, 114.0, 113.1, 108.0, 55.2,
39.4, 29.3; MS (ESI, negative ion mode): m/z 287 (MKH)K.
Analysis found: C, 66.62; H, 5.62%. Calcd for C16H16O5: C,
66.66; H, 5.59%.
4.3.3. 7-Hydroxy-3-[(3,4-dihydroxyphenyl)methyl]-4H-
chromen-4-one (4c). Colorless powder (695 mg, 82%),
mp 192–194 8C; IR (KBr): 3393, 1627, 1239, 1180, 1113,
1
967 cmK1; H NMR (DMSO-d6): d 10.73 (1H, s, Ar-OH),
8.72 (1H, s, Ar-OH), 8.61 (1H, s, Ar-OH), 8.07 (1H, s, H-2),
7.86 (1H, d, JZ8.8 Hz, H-5), 6.88 (1H, dd, JZ8.8, 2.2 Hz,
H-6), 6.79 (1H, d, JZ2.2 Hz, H-8),0 6.63 (1H, d, JZ2.1 Hz,
H-20), 6.59 (1H, d, JZ8.3 Hz, H-5 ), 6.51 (1H, dd, JZ8.3,
2.1 Hz, H-60), 3.47 (2H, s, H-9); 13C NMR (CDCl3C
DMSO-d6): d 176.4, 162.1, 157.8, 152.3, 144.4, 142.9,
129.9, 126.6, 123.7, 119.8, 116.3, 115.7, 115.1, 114.6,
102.0, 30.3; MS (ESI, negative ion mode): m/z 283
(MKH)K. Analysis found: C, 67.58; H, 4.29%. Calcd for
C16H12O5: C, 67.60; H, 4.26%.
4.2.8. 1-(2,4,6-Trihydroxyphenyl)-3-(4-hydroxyphenyl)-
propan-1-one (3h). Pale yellow solid (245 mg, 30%), mp
258–260 8C (lit.19 mp 257–258 8C); IR (KBr): 3268, 1630,
1606, 1296, 1209, 1163, 1076 cmK1; 1H NMR (DMSO-d6):
d 12.23 (2H, s, Ar-OH), 10.36 (1H, s,0 A0r-OH), 9.13 (1H, s,
Ar-OH), 7.000 (2H, d, JZ8.3 Hz, H-2 ,6 ), 6.65 (2H, d, JZ
8.3 Hz, H-3 ,50), 5.79 (2H, s, H-300, 500), 3.20 (2H, t, JZ
7.8 Hz, H-3), 2.74 (2H, t, JZ7.8 Hz, H-2); 13C NMR
(DMSO-d6): d 204.4, 164.8, 164.4, 155.6, 131.9, 129.4,
115.3, 103.9, 94.9, 45.7, 29.6; MS (ESI, negative ion mode):
m/z 273 (MKH)K.
4.3.4. 7-Hydroxy-3-[(3,4-dimethoxyphenyl)methyl]-4H-
chromen-4-one (4d). Colorless powder (815 mg, 87%),
mp 180–182 8C; IR (KBr): 3245, 1632, 1262, 1244, 1175,
1140, 1094, 1026, 963 cmK1; 1H NMR (DMSO-d6): d 10.62
(1H, s, Ar-OH), 8.01 (1H, s, H-2), 7.88 (1H, d, JZ8.8 Hz,
H-5), 6.78–6.90 (5H, m, Ar-H), 3.75 (3H, s, Ar-OCH3), 3.72
(3H, s, Ar-OCH3), 3.61 (2H, s, H-9); 13C NMR (CDCl3C
DMSO-d6): d 176.0, 162.3, 157.8, 152.4, 148.4, 147.1,
131.4, 126.6, 123.3, 120.5, 116.3, 114.7, 112.2, 111.2,
102.0, 55.4, 55.3, 30.6; MS (ESI, negative ion mode): m/z
311 (MKH)K. Analysis found: C, 69.19; H, 5.21%. Calcd
for C18H16O5: C, 69.22; H, 5.16%.
4.3. General procedure for homoisoflavonoids (4)
A mixture of 3 (3 mmol) and BF3$Et2O (1.2 mL, 9 mmol)
was cooled to 10 8C and DMF (4.6 mL) was added drop
wise for 5 min. In another flask, DMF (8 mL) was cooled to
10 8C and PCl5 (0.939 g, 4.5 mmol) was added in small
portions. The mixture was then allowed to stand to 55 8C for
20 min. The light yellow colored solution containing N,N0-
dimethyl(chloromethylene)ammonium chloride was then
added to the above reaction mixture slowly at 20–25 8C. The
mixture was stirred at rt for 2 h and poured into boiling dil
HCl slowly and cooled. The solution was extracted with
EtOAc (3!50 mL) and the combined EtOAc layer was
washed with water (20 mL), brine (20 mL) and dried over
sodium sulfate. The residue obtained after evaporation of
the solvent was chromatographed over silica gel column
using chloroform–methanol mixtures as eluent to give 4a–h.
4.3.5. 7-Hydroxy-3-[(2,4-dimethoxyphenyl)methyl]-4H-
chromen-4-one (4e). Colorless powder (730 mg, 78%),
mp 182–184 8C; IR (KBr): 3224, 1631, 1241, 1207, 1158,
1
1124, 1040 cmK1; H NMR (DMSO-d6): d 10.72 (1H, s,
Ar-OH), 7.86 (1H, d, JZ8.8 Hz, H-5), 7.85 (1H, s, H-2),
7.02 (1H, d, JZ8.3 Hz, H-60), 6.88 (1H, dd, JZ8.8, 2.0 Hz,
H-6), 6.79 (1H, d, JZ2.0 Hz, H-8), 6.51 (1H, d, JZ2.1 Hz,

V. Siddaiah et al. / Tetrahedron 62 (2006) 841–846
845
H-30), 6.42 (1H, dd, JZ8.3, 2.1 Hz, H-50), 3.77 (3H, s,
Ar-OCH3), 3.70 (3H, s, Ar-OCH3), 3.51 (2H, s, H-9); MS
(ESI, negative ion mode): m/z 311 (MKH)K. Analysis
found: C, 69.18; H, 5.20%. Calcd for C18H16O5: C, 69.22;
H, 5.16%.
converted into mM. All the tests were run in triplicate and
averaged.
4.4.2. DPPH free radical scavenging activity. DPPH
radical scavenging activity was measured based on the
reduction of methanolic solution of the colored DPPH.26
Free radical scavenging ability of the test drug in ethanol
added to the methanolic solution of DPPH is inversely
proportional to the difference in initial and final absorption
of DPPH solution at 516 nm. Drug activity is expressed as
the 50% inhibitory concentration (IC50). The reaction
mixture contained 1!10K4 mM methanolic solution of
DPPH and various concentrations of test drugs. The
percentage inhibition was determined by comparing the
absorbance values of test and control tubes. IC50 values
were obtained from the plot, drawn for concentration in
microgram versus percentage inhibition.
4.3.6. 7,8-Dihydroxy-3-[(4-hydroxyphenyl)methyl]-4H-
chromen-4-one (4f). Colorless powder (680 mg, 80%),
mp 251–253 8C; IR (KBr): 3458, 1628, 1201, 1175, 1156,
1
1047, 985 cmK1; H NMR (DMSO-d6): d 10.17 (1H, s,
Ar-OH), 9.15 (2H, br s, 2!Ar-OH), 8.14 (1H, s, H-2), 07.37
(1H, d, JZ8.6 Hz, H-5), 7.07 (2H, d, JZ8.3 Hz, H-2 ,60),
6.91 (1H, d, JZ8.6 Hz, H-6), 6.65 (2H, d, JZ8.3 Hz,
H-30,50), 3.56 (2H, s, H-9); 13C NMR (CDCl3CDMSO-d6):
d 176.1, 155.6, 152.9, 149.9, 147.1, 132.9, 129.9, 129.5,
123.0, 117.1, 115.2, 115.0, 114.1, 30.0; MS (ESI, negative
ion mode): m/z 283 (MKH)K. Analysis found: C, 67.57; H,
4.30%. Calcd for C16H12O5: C, 67.60; H, 4.26%.
4.3.7. 7,8-Dihydroxy-3-[(4-methoxyphenyl)methyl]-4H-
chromen-4-one (4g). Colorless powder (725 mg, 81%),
mp 252–254 8C; IR (KBr): 3320, 3150, 1631, 1241, 1172,
1155, 1047, 980 cmK1; 1H NMR (DMSO-d6): d 10.25 (1H,
s, Ar-OH), 9.39 (1H, s, Ar-OH), 8.21 (1H, s, H-2),07.38 (1H,
d, JZ8.8 Hz, H-5), 7.21 (2H, d, JZ8.3 Hz, H-2 ,60), 06.92
(1H, d, JZ8.8 Hz, H-6), 6.82 (1H, d, JZ8.3 Hz, H-3 ,50),
3.70 (3H, s, Ar-OCH3), 3.61 (2H, s, H-9); 13C NMR
(CDCl3CDMSO-d6): d 176.2, 157.4, 152.1, 149.4, 146.8,
132.5, 130.9, 129.3, 122.7, 117.0, 115.1, 113.7, 113.3, 54.6,
30.0; MS (ESI, negative ion mode): m/z 297 (MKH)K.
Analysis found: C, 68.41; H, 4.79%. Calcd for C17H14O5: C,
68.45; H, 4.73%.
Acknowledgements
The authors thank Sri G. Ganga Raju, Chairman, and Mr. G.
Rama Raju, Director, of Laila Impex for encouragement and
to the CSIR, New Delhi for the award of SRF to one of the
authors (V.S.).
References and notes
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