Isoaurones: synthesis and stereochemical assignments of geometrical isomers

Article abstract of DOI:10.1016/j.tet.2006.08.048

A series of isoaurones have been synthesized for the first time from substituted acetophenones via benzo-2(3H)-furanone in three steps. Geometrical isomers of the isoaurones were separated. The differences in the proton and carbon NMR spectra of the E- and Z-isoaurones afford a useful method for distinguishing between the two isomers. Marginalin, a metabolite of Dytiscus marginalis has been synthesized and the spectral data of the synthetic E-isomer were in good agreement with those of the natural product. The antioxidant activity of isoaurones was determined by superoxide free radical (NBT) method and isoaurones 12 and 13 displayed excellent antioxidant activity.

Full text of DOI:10.1016/j.tet.2006.08.048

Tetrahedron 62 (2006) 9855–9860
Isoaurones: synthesis and stereochemical assignments of
geometrical isomers*
Somepalli Venkateswarlu, Gopala K. Panchagnula, Mothukuri Bala Guraiah
*
and Gottumukkala V. Subbaraju
Laila Research Centre, Unit 1, Phase III, Jawahar Autonagar, Vijayawada 520 007, Andhra Pradesh, India
Received 23 March 2006; revised 1 August 2006; accepted 11 August 2006
Available online 1 September 2006
Abstract—A series of isoaurones have been synthesized for the first time from substituted acetophenones via benzo-2(3H)-furanone in three
steps. Geometrical isomers of the isoaurones were separated. The differences in the proton and carbon NMR spectra of the E- and Z-isoaurones
afford a useful method for distinguishing between the two isomers. Marginalin, a metabolite of Dytiscus marginalis has been synthesized and
the spectral data of the synthetic E-isomer were in good agreement with those of the natural product. The antioxidant activity of isoaurones
was determined by superoxide free radical (NBT) method and isoaurones 12 and 13 displayed excellent antioxidant activity.
Ó 2006 Published by Elsevier Ltd.
1. Introduction
isoaurones are limited.11 Evenan attempted synthesis of mar-
ginalin12 by Barbier did not give the natural product but gave
an isomer of the natural marginalin. Isoaurostatin, a novel
topoisomerase I inhibitor, was recently isolated from the cul-
ture filtrate of Thermomonospora alba strain No. 1520 and
assigned E-configuration based on HMBC and NOE spec-
tra.8 We have synthesized both isomers of isoaurostatin,13
but the spectral data did not match with those of the natural
product and its structure was revised as daidzein, a well
known isoflavone. Recently, isoaurones were found as poten-
tial anticancer agents,14 but the authors did not assign the
configuration. The stereochemistry of isoaurones has not
been studied in detail except by converting E/Z-phenyl cin-
namic acids into corresponding isoaurones.15 In view of the
importance of stereochemistry for the biological activity and
lack of reports in the literature on the stereochemical assign-
ments of isoaurones by NMR spectroscopy, in this paper we
have presented the details of (a) isoaurones synthesis, isola-
tion of stereoisomers, and spectroscopic methods to establish
the stereochemistry at the double bond and (b) the synthesis
of marginalin, a metabolite of Dytiscus marginalis (Coleop-
tera) and the establishment of its stereochemistry as E.
Aurones (1), 2-benzylidenebenzofuran-3(2H)-ones, and iso-
aurones (2), 3-benzylidenebenzofuran-2(3H)-ones, are natu-
rally occurring yellow pigments of plants and are structurally
related to flavonoids1 (Fig. 1). In addition to the pigmentation
role, they have been described as phytoalexins used by the
plant as defense agents against various infections.2 A few
methods of syntheses were reported in the literature for
aurones,2–4 and Z-isomers are thermodynamically more sta-
ble and are the only products obtained using acidic or basic
reagents. The stereochemistry of aurones was established by
proton5 and carbon6 NMR spectroscopy and spectroscopies.
Naturally occurring isoaurones are growing recently and
a few compounds were reported, namely, marginalin,7 iso-
aurostatin,8 4,6,40-trihydroxyisoaurone,9 and pterocarpo-
side, the first isoaurone C-glucoside.10 Synthetic studies on
O
O
O
O
Aurone (1)
Isoaurone (2)
2. Results and discussion
2.1. Synthesis
Figure 1. General structures of aurone and isoaurone.
*
Laila Communication # 57.
Keywords: Isoaurone; 3-Benzylidenebenzofuran-2(3H)-one; Synthesis;
Stereochemistry; Marginalin; Antioxidant.
* Corresponding author. Tel.: +91 866 2541303; fax: +91 866 2546216;
e-mail: subbarajugottumukkala@hotmail.com
The general route for the synthesis of isoaurones involves
the acid or base catalyzed condensation of substituted
2(3H)-benzofuranone with aromatic aldehydes. The desired
substituted benzofuranones were synthesized as follows.
0040–4020/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tet.2006.08.048

9856
S. Venkateswarlu et al. / Tetrahedron 62 (2006) 9855–9860
Table 1. IR data of E- and Z-isoaurones
Willgerodt–Kindler reaction of 2-hydroxy-5-methoxyaceto-
phenone (3a) with sulfur and morpholine under phase trans-
fer catalytic conditions16 gave phenylacetic acid derivative
4a in 64% yield. Lactonisation of 4a in the presence of
phosphorus oxychloride17 yielded 5-methoxybenzo-2(3H)-
furanone (5a) in 85% yield. Demethylation of 5a using
pyridine hydrochloride18 furnished 5-hydroxybenzo-2(3H)-
furanone (5c) in 66% yield (Scheme 1). The 5-methyl
benzofuranone (5b) was prepared in a similar fashion. Con-
densation of 5a, b or c with substituted benzaldehydes using
KOH as a base gave isoaurones (6–13). In all examples, two
isomers (E and Z) were formed, which could be separated by
column chromatography, and are well characterized by their
spectral data (IR, NMR, and Mass). But the 1H NMR spectra
of isoaurones 12 and 13 showed them to be a mixture of two
isomers as also confirmed by HPLC. Attempts to separate
these were not successful even by preparative HPLC. It is
known that in aurones the Z-isomer is thermodynamically
more stable but in isoaurones more of E-isomer is formed
in our own studies as well in that of others.19 Perhaps the
interactions of carbonyl and the pendant aryl ring are
minimum in the case of E-isomer.
Compd no.
C]O (lmax, cmꢀ1
)
E
Z
6
7
8
9
10
1778
1740
1740
1780
1778
1721
1762
1760
1756
1754
Table 2. 1H NMR data of E- and Z-isoaurones
Compd no.
E
Z
H-4
H-10
H-20,60
H-4
H-10
H-20,60
6
7
8
9
10
7.36
7.16
7.19
7.19
6.95
7.79
7.81
7.72
7.77
7.72
6.91
7.67
7.64
7.62
7.67
7.02
7.01
7.02
7.00
6.91
7.45
7.50
7.49
7.46
7.48
7.68
8.25
8.13
8.12
8.24
lower field than the corresponding proton in Z-isomers. In
all examples, the H-4 proton in E-isomer appeared at a lower
field (ca. 0.04–0.34 ppm) than the corresponding proton in
Z-isomer and the difference is useful to assign the configura-
tion. Most importantly, in all Z-isomers, the protons (H-20
and H-60) of pendant aryl units appeared as a doublet at
much lower field (ca. 0.49–0.77 ppm) than the correspond-
ing protons in E-isomers and this chemical shift difference
is large enough to assign the configuration.
The carbonyl absorptions in IR spectra of E- and Z-iso-
aurones are presented in Table 1. The data revealed that
within the particular example, the difference is quite large
to distinguish each other, but the data are not suitable for
assigning the configuration.
The proton NMR data of E- and Z-isoaurones are presented
in Table 2. As a rule in a,b-unsaturated carbonyl com-
pounds, the anisotropic, diamagnetic deshielding of the car-
bonyl group causes the olefinic proton cis to the carbonyl to
give an absorption at a lower field (ca. 1 ppm) than in the
trans arrangement, so that the assignment of configuration
can be made on the basis of the chemical shift of the olefinic
proton.20,21 The present study also reveals that the olefinic
proton (H-10) in E-isomers gave a singlet as expected at
The carbon NMR data of E- and Z-isoaurones (Table 3) re-
vealed that the chemical shift differences of olefinic carbon
(C-10) are very little and are not useful to distinguish
between the two isomers. In all E-isomers, the carbonyl
absorption (w169 ppm) is at a lower field (ca. 3 ppm) than
the corresponding carbonyl in Z-isomers (w166 ppm) and
this difference could be used to assign the configuration at
the double bond in isoaurones. The other carbons useful in
OH
O
OH
COOH
(i)
(ii)
(iii)
O
82-95%
55-64%
25-68%
R1
R1
R1
O
3a R1=OCH3
b R1=CH3
4a R1=OCH3
b R1=CH3
5a R1=OCH3
b R1=CH3
c R1=OH
7
O 1
8
O
O
O
5
2
R2
R3
9
R1
6
7
2'
4
R1
R1=OH, R2=R3=R4=OCH3
R1=OH, R2=R4=H, R3=F
R1=OH, R2=R4=H, R3=Cl
+
4
10
6'
10
R4
6'
2'
8
R4
4'
R3
R1=OCH3, R2=R4=H, R3=Cl
R1=CH3, R2=R4=H, R3=OCH3
R2
9
10
E
Z
R1=R3=OH, R2=R4=H
R1=R2=R3=OH, R4=H
R1=R2=R3=R4=OH
11
12
13
Scheme 1. Reagents and conditions: (i) S, morpholine, p-TSA, 20% NaOH, PTC, reflux, 16 h, 55–64%; (ii) POCl3, DCE, rt, 15 h, 82–85%; (iii) substituted
benzaldehyde, KOH, EtOH, rt, 10 h, 25–68%.

S. Venkateswarlu et al. / Tetrahedron 62 (2006) 9855–9860
9857
Table 3. 13C NMR data of E- and Z-isoaurones
2.2. Antioxidant activity
Compd no.
E
Z
We have determined the antioxidant activity of isoaurones
by nitro blue tetrazolium (NBT)22,23 free radical scavenging
method. The IC50 values of the active compounds are pre-
sented in Table 5. From the data, isoaurones 12 and 13
having catechol and pyrogallol moieties showed good activ-
ity and were several fold potent in comparison with the com-
mercially available antioxidants like vitamin C and BHA.
C-2
C-20,60
C-2
C-20,60
6
7
8
9
10
169.3
169.4
169.2
169.0
169.7
106.5
131.5
130.7
130.6
131.6
166.5
166.5
166.4
166.2
166.7
109.6
134.3
133.2
133.2
134.4
Table 5. Antioxidant activity of isoaurones
this aspect are C-20 and C-60 carbons of the pendant aryl unit.
In all examples, the C-20 and C-60 carbons of Z-isomers
appeared at a lower field (ca. 2.3–3.1 ppm) than the corre-
sponding carbons in E-isomers.
Compd
NBT superoxide scavenging
activity (IC50 in mM)
Marginalin (11)
12
13
Vitamin C
BHA
59.0
40.2
24.7
852
The stereochemistry of the double bond at C-3 and C-10 of
isoaurones was confirmed further by the double irradiation
experiments. Irradiation of H-4 (7.19, 1H, d, J¼2.4 Hz) in
compound 8E showed positive NOE on H-20,60 (7.64, 2H,
d, J¼8.2 Hz). Similarly, irradiation of H-20,60 resulted in
positive NOE on H-4. Based on the above, H-4 and the
aryl ring are oriented spatially close to each other and con-
firm ‘E’ stereochemistry for the double bond between C-3
and C-10.
966
BHA: butylated hydroxyanisole. The lower the IC50 values, the higher is the
antioxidant activity.
3. Conclusions
In summary, we have synthesized a series of isoaurones for
the first time from substituted acetophenones via benzo-
2(3H)-furanone in three steps and their geometrical isomers
were separated. The configuration at the double bond could
be assigned on the basis of proton and carbon NMR spectral
data. The H-20,60 protons of pendant aryl unit in Z-isomers
appeared as a doublet at much lower field (ca. 0.49–
0.77 ppm) than the corresponding protons in E-isomers.
Marginalin (11), isolated from D. marginalis, has been syn-
thesized and its stereochemistry has been confirmed as E.
The isoaurones 12 and 13 were potent antioxidants as con-
firmed by superoxide (NBT) free radical scavenging method.
Similarly, irradiation of H-4 (7.02, 1H, br s) in compound 8Z
showed positive NOE on H-10 (7.49, 1H, s). Further irradi-
ation of the signal corresponding to H-20,60 (8.13, 2H, d,
J¼8.1 Hz) did not show any effect on H-4. Thus, H-4 and
H-10 are spatially close and confirm ‘Z’ stereochemistry
for the double bond at C-3 and C-10.
Marginalin (11) was synthesized through base catalyzed
condensation of 5-hydroxybenzo-2(3H)-furanone (5c) with
4-hydroxybenzaldehyde in 60% yield (Scheme 1). The H
1
NMR spectrum of 11 showed that it is a mixture of two
isomers and was confirmed by HPLC (E/Z–70:30). The con-
densation reaction was tried with other reagents such as tri-
ethylamine, acetic anhydride, p-TSA, and neutral alumina.
But in all cases, we isolated a mixture of E/Z-isomers. The
E-isomer was obtained in 96% purity by repeated crystalliza-
tions, but we could isolate the Z-isomer in only 75% purity,
however, the spectral data could be interpreted well. The
configuration of both the isomers has been assigned based
on the foregoing analogy, i.e. H-20,60 protons in Z-isomer
appeared as doublet at d 8.27, whereas the same protons in
E-isomer appeared at d 7.70. The 1H NMR data of synthetic
E-isomer 11 agree well with those of natural 11 and con-
firmed the natural product stereochemistry as E (see Table
4). Interestingly, the data on synthetic marginalin reported
earlier12 did not match either with E-isomer or Z-isomer
and perhaps required further scrutiny.
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 Spectropho-
tometer. 1H NMR (300 MHz) and 13C NMR (75 MHz) spec-
tra were recorded on Jeol JNM l-300 spectrometer using
TMS as internal reference and the values for chemical shifts
(d) are given in parts per million (ppm) and coupling con-
stants (J) in hertz (Hz). In the 13C NMR spectra, the nature
of the carbons (C, CH, CH2 or CH3) was determined using
DEPT-135, and are given in parentheses. Mass spectra
were recorded on Agilent 1100 LC/MSD and elemental
Table 4. 1H NMR data of marginalin (DMSO-d6)
Position
Synthetic 11E
Synthetic 11Z
Z-Marginalin reported (Ref. 12)
Natural marginalin
4
6
7
10
20,60
30,50
7.31 (d, 2.4)
6.79 (dd, 2.4, 8.6)
7.09 (d, 8.6)
7.72 (s)
7.70 (d, 8.6)
6.96 (d, 8.6)
7.16 (d, 2.4)
6.73 (dd, 2.4, 8.6)
6.99 (d, 8.6)
7.86 (s)
8.27 (d, 8.8)
6.90 (d, 8.8)
6.56 (d, 3.0)
5.80 (dd, 3.0, 8.0)
6.16 (d, 8.0)
6.72 (s)
7.13 (d, 8.0)
5.90 (d, 8.0)
7.30 (d, 3.0)
6.79 (dd, 3.0, 8.0)
7.07 (d, 8.0)
7.72 (s)
7.68 (d, 8.0)
6.96 (d, 8.0)

9858
S. Venkateswarlu et al. / Tetrahedron 62 (2006) 9855–9860
analysis on a Vario El Elementar instrument. HPLC was
recorded by a Shimadzu SCL-10A instrument under the fol-
lowing conditions: column, Phenomenex C18, 250 mmꢁ
4.6 mm; flow rate, 1 mL/min; detection at 384 nm; mobile
phase, 0.1% phosphoric acid/acetonitrile (65:35, v/v); reten-
tion time for 11E, 19.62 and for 11Z, 17.92 min. Acme silica
gel G and silica gel (100–200 mesh) were used for analytical
TLC and column chromatography, respectively. For antioxi-
dant activity procedure see Ref. 23.
4.3.2. 5-Methyl-3-hydrobenzo[b]furan-2-one (5b). Color-
less powder (2.2 g, 82%), mp 66–68 ꢂC (lit.26 mp 68.5–
71.5 ꢂC); IR (neat): 3399, 2920, 1809, 1606, 1156, 1083,
1
1027 cmꢀ1; H NMR (CDCl3): d 2.38 (3H, s, Ar–CH3),
3.69 (2H, s, H-3), 6.93–6.95 (2H, m, Ar–H), 7.15 (1H, d,
J¼7.9 Hz, Ar–H); MS (ESI, negative scan): m/z 147
(MꢀH)ꢀ.
4.4. 5-Hydroxy-3-hydrobenzo[b]furan-2-one (5c)
4.2. Phenylacetic acid derivative 4. General procedure
A mixture of 5a (1 g) and pyridine hydrochloride (10 g) was
stirred in N2 atmosphere at 180–190 ꢂC for 3 h. The cooled
reaction mixture was diluted with ice cold water (50 mL),
acidified with dil HCl (10%, 20 mL), and extracted with
EtOAc (3ꢁ50 mL). The combined EtOAc layer was washed
with brine (25 mL) and dried over sodium sulfate. The resi-
due obtained after evaporation of the solvent was chromato-
graphed over silica gel column using chloroform–methanol
mixtures as eluents to give 5c as a light yellow powder
(600 mg, 66%), mp 184–186 ꢂC (lit.27 mp 190 ꢂC); IR
(neat): 3322, 2923, 1761, 1602, 1242, 1149, 1074, 949,
A mixture of 3 (50 mmol), sulfur (3.2 g, 100 mmol), morpho-
line (15 mL, 150 mmol), and p-toluenesulfonic acid (0.3 g,
1.75 mmol) was refluxed under constant stirring at 120–
130 ꢂC for 8 h. After completion of the reaction, the mixture
was allowed to cool and 20% aq NaOH (70 mL) and tetra-
butylammonium bromide (216 mg, 1.25 mmol) were added
and hydrolysis was continued for further 8 h at 100 ꢂC. The
cooled reaction mixture was filtered and the filtrate was acid-
ified with HCl to pH 2. The solution was extracted with
EtOAc (3ꢁ150 mL) and the combined organic layer was
washed with water (100 mL), brine (100 mL), and dried
over sodium sulfate. The residue obtained after evaporation
of the solvent was chromatographed over silica gel column
using hexane–EtOAc mixtures as eluents to give 4.
1
890 cmꢀ1; H NMR (DMSO-d6): d 3.84 (2H, s, H-3), 6.65
(1H, dd, J¼8.6, 1.6 Hz, H-6), 6.75 (1H, d, J¼1.6 Hz, H-4),
6.95 (2H, d, J¼8.6 Hz, H-7), 9.28 (1H, s, Ar–OH); MS
(ESI, negative scan): m/z 149 (MꢀH)ꢀ.
4.5. 3-Benzylidenebenzofuran-2(3H)-ones (6–13).
General procedure
4.2.1. 2-(2-Hydroxy-5-methoxyphenyl)acetic acid (4a).
Colorless powder (5.9 g, 64%), mp 128–130 ꢂC (lit.24 mp
131–133 ꢂC); IR (neat): 3380, 1720, 1204, 1159, 1025,
To a solution of substituted 3-hydrobenzo[b]furan-2-one
(1.5 mmol) in ethanol (15 mL) was added substituted benz-
aldehyde (3.0 mmol) and the pH was brought to 8 with few
drops of ethanolic KOH solution. The mixture was stirred
at rt for 1 h and again the pH was made 8 with few drops of
KOH solution and the mixture was stirred at rt for 14 h.
The reaction mixture was acidified with dilute aqueous HCl
(10%, 20 mL) and extracted with EtOAc (3ꢁ50 mL). The
combined EtOAc layer was washed with water (20 mL),
brine (20 mL), and dried over sodium sulfate. The residue ob-
tained after evaporation of the solvent was chromatographed
over silica gel column using hexane–EtOAc mixtures as
eluents to give isoaurones.
1
819 cmꢀ1; H NMR (CDCl3): d 3.67 (2H, s, Ar–CH2–),
3.75 (3H, s, Ar–OCH3), 6.70–6.76 (2H, m, Ar–H), 6.84
(1H, d, J¼8.6 Hz, Ar–H); MS (ESI, negative scan): m/z
181 (MꢀH)ꢀ.
4.2.2. 2-(2-Hydroxy-5-methylphenyl)acetic acid (4b).
Colorless powder (4.5 g, 55%), mp 118–120 ꢂC (lit.25 mp
123.5 ꢂC); IR (neat): 3458, 1699, 1622, 1290, 1219, 1157,
1
1109, 962 cmꢀ1; H NMR (CDCl3): d 2.28 (3H, s, Ar–
CH3), 3.65 (2H, s, Ar–CH2–), 6.71–6.73 (2H, m, Ar–H),
7.00 (1H, d, J¼8.0 Hz, Ar–H); MS (ESI, negative scan):
m/z 165 (MꢀH)ꢀ.
4.3. 3-Hydrobenzo[b]furan-2-one derivative 5. General
procedure
4.5.1. 3-[(3,4,5-Trimethoxyphenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (6E). Yellow powder (187 mg, 38%),
mp 188–190 ꢂC; IR (KBr): 3479, 1778, 1641, 1242, 1125,
1102, 999, 972 cmꢀ1; 1H NMR (CDCl3): d 3.90 (6H, s, Ar–
OCH3), 3.95 (3H, s, Ar–OCH3), 4.90 (1H, br s, Ar–OH),
6.81 (1H, dd, J¼8.6, 2.5 Hz, H-6), 6.91 (2H, s, H-20,60),
7.02 (1H, d, J¼8.6 Hz, H-7), 7.36 (1H, d, J¼2.5 Hz, H-4),
7.79 (1H, s, H-10); 13C NMR (CDCl3): d 169.3 (C-2),
153.5 (C-5), 152.9 (C-30,50), 147.3 (C-40), 140.1 (C-10),
139.4 (C-8), 128.9 (C-10), 121.9 (C-3), 121.8 (C-9), 117.6
(C-4), 111.2 (C-6), 109.2 (C-7), 106.5 (C-20,60), 60.6
(Ar–OCH3), 55.9 (Ar–OCH3); MS (ESI, positive scan): m/z
329 (M+H)+. Analysis found: C, 65.79; H, 4.96%. Calcd
for C18H16O6: C, 65.85; H, 4.91%.
A mixture of 4 (3 g) and phosphorus oxychloride (15 mL) in
dichloroethane (90 mL) was stirred at rt for 16 h. The reac-
tion mixture was diluted with water (50 mL) and extracted
with chloroform (3ꢁ30 mL) and the combined chloroform
layer was washed with water (20 mL), sodium bicarbonate
(20 mL), and dried over sodium sulfate. The residue ob-
tained after evaporation of the solvent was chromatographed
over silica gel column using hexane–EtOAc mixtures as
eluents to give 5.
4.3.1. 5-Methoxy-3-hydrobenzo[b]furan-2-one (5a). Light
yellow powder (2.3 g, 85%), mp 98–100 ꢂC (lit.24 mp 95–
98 ꢂC); IR (neat): 2965, 1801, 1605, 1283, 1253, 1222,
4.5.2. 3-[(3,4,5-Trimethoxyphenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (6Z). Yellow powder (74 mg, 15%),
mp 189–191 ꢂC; IR (KBr): 3340, 1721, 1607, 1258, 1125,
1
1149, 1069, 1025, 921, 858, 814 cmꢀ1; H NMR (CDCl3):
d 3.72 (2H, s, H-3), 3.79 (3H, s, Ar–OCH3), 6.81–6.85 (2H,
m, Ar–H), 7.01 (1H, d, J¼8.6 Hz, Ar–H); MS (ESI, positive
scan): m/z 187 (M+Na)+.
1
1082, 1004 cmꢀ1; H NMR (CDCl3): d 3.96 (3H, s, Ar–
OCH3), 3.97 (6H, s, Ar–OCH3), 4.79 (1H, br s, Ar–OH),

S. Venkateswarlu et al. / Tetrahedron 62 (2006) 9855–9860
9859
6.78 (1H, dd, J¼8.6, 2.5 Hz, H-6), 6.98 (1H, d, J¼8.6 Hz, H-
7), 7.02 (1H, d, J¼2.5 Hz, H-4), 7.45 (1H, s, H-10), 7.68 (2H,
s, H-20,60); 13C NMR (CDCl3): d 166.5 (C-2), 153.8 (C-5),
152.3 (C-30,50), 145.5 (C-40), 140.5 (C-8), 139.9 (C-10),
128.5 (C-10), 125.8 (C-3), 119.9 (C-9), 116.4 (C-4), 110.6
(C-6), 109.6 (C-20,60), 105.7 (C-7), 60.5 (Ar–OCH3), 55.8
(Ar–OCH3); MS (ESI, positive scan): m/z 329 (M+H)+.
Analysis found: C, 65.81; H, 4.95%. Calcd for C18H16O6:
C, 65.85; H, 4.91%.
8.13 (2H, d, J¼8.1 Hz, H-20,60), 9.0 (1H, br s, Ar–OH); 13C
NMR (CDCl3+DMSO-d6): d 166.4 (C-2), 154.1 (C-5),
146.3 (C-8), 138.1 (C-10), 136.8 (C-10), 133.2 (C-20,60),
131.7 (C-40), 128.6 (C-30,50), 125.5 (C-3), 122.1 (C-9),
117.4 (C-4), 111.1 (C-6), 106.3 (C-7); MS (ESI, negative
scan): m/z 271 (MꢀH)ꢀ, 273 (MꢀH)ꢀ. Analysis found: C,
66.04; H, 3.36%. Calcd for C15H9ClO3: C, 66.07; H, 3.33%.
4.5.7. 3-[(4-Chlorophenyl)methylene]-5-methoxy-
benzo[b]furan-2-one (9E). Yellow powder (150 mg, 35%),
mp 156–158 ꢂC; IR (KBr): 1780, 1619, 1236, 1209, 1110,
4.5.3. 3-[(4-Fluorophenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (7E). Yellow powder (135 mg, 35%),
mp 199–201 ꢂC; IR (KBr): 3294, 1740, 1625, 1288, 1220,
1
1086, 1033, 907 cmꢀ1; H NMR (CDCl3): d 3.73 (3H, s,
Ar–OCH3), 6.90 (1H, dd, J¼8.7, 2.2 Hz, H-6), 7.05 (1H, d,
J¼8.7 Hz, H-7), 7.19 (1H, d, J¼2.2 Hz, H-4), 7.48 (2H, d,
J¼8.4 Hz, H-30,50), 7.62 (2H, d, J¼8.4 Hz, H-20,60), 7.77
(1H, s, H-10); 13C NMR (CDCl3): d 169.0 (C-2), 155.8 (C-
5), 148.8 (C-8), 139.2 (C-10), 136.5 (C-10), 132.3 (C-40),
130.6 (C-20,60), 129.2 (C-30,50), 123.3 (C-3), 122.0 (C-9),
116.4 (C-4), 111.7 (C-6), 108.5 (C-7), 55.8 (Ar–OCH3); MS
(ESI, positive scan): m/z 287 (M+H)+, 289 (M+H)+. Analysis
found: C, 67.01; H, 3.89%. Calcd for C16H11ClO3: C, 67.03;
H, 3.87%.
1
1150, 1109, 1006 cmꢀ1; H NMR (CDCl3): d 4.79 (1H, br
s, Ar–OH), 6.83 (1H, dd, J¼8.6, 2.5 Hz, H-6), 7.02 (1H, d,
J¼8.6 Hz, H-7), 7.16 (1H, d, J¼2.5 Hz, H-4), 7.21 (2H,
dd, J¼8.6 Hz, H-30,50), 7.67 (2H, dd, J¼8.6, 5.5 Hz, H-
20,60), 7.81 (1H, s, H-10); 13C NMR (CDCl3+DMSO-d6):
1
d 169.4 (C-2), 163.5 (d, JCF¼252 Hz, C-40), 153.5 (C-5),
3
147.8 (C-8), 138.9 (C-10), 131.5 (d, JCF¼9 Hz, C-20,60),
4
130.2 (d, JCF¼3 Hz, C-10), 123.1 (C-3), 121.9 (C-9),
2
118.1 (C-4), 116.0 (d, JCF¼22 Hz, C-30,50), 111.4 (C-6),
109.5 (C-7); MS (ESI, negative scan): m/z 255 (MꢀH)ꢀ.
Analysis found: C, 70.28; H, 3.57%. Calcd for C15H9FO3:
C, 70.31; H, 3.54%.
4.5.8. 3-[(4-Chlorophenyl)methylene]-5-methoxy-
benzo[b]furan-2-one (9Z). Yellow powder (40 mg, 9%),
mp 168–170 ꢂC; IR (KBr): 1756, 1611, 1281, 1215, 1053,
1
4.5.4. 3-[(4-Fluorophenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (7Z). Yellow powder (38 mg, 10%),
mp 206–208 ꢂC; IR (KBr): 3339, 1762, 1605, 1244, 1168,
1116, 1049, 990, 924 cmꢀ1; 1H NMR (CDCl3): d 4.81 (1H,
br s, Ar–OH), 6.80 (1H, dd, J¼8.6, 2.5 Hz, H-6), 6.98 (1H,
d, J¼8.6 Hz, H-7), 7.01 (1H, d, J¼2.5 Hz, H-4), 7.16 (2H,
dd, J¼8.6 Hz, H-30,50), 7.50 (1H, s, H-10), 8.25 (2H, dd,
J¼8.6, 5.5 Hz, H-20,60); 13C NMR (CDCl3+DMSO-d6):
1034, 980 cmꢀ1; H NMR (CDCl3): d 3.84 (3H, s, Ar–
OCH3), 6.86 (1H, dd, J¼8.7, 2.2 Hz, H-6), 6.99 (1H, d,
J¼8.7 Hz, H-7), 7.00 (1H, d, J¼2.2 Hz, H-4), 7.41 (2H, d, J¼
8.1 Hz, H-30,50), 7.46 (1H, s, H-10), 8.12 (2H, d, J¼8.1 Hz,
H-20,60); 13C NMR (CDCl3): d 166.2 (C-2), 156.4 (C-5),
147.3 (C-8), 138.4 (C-10), 137.3 (C-10), 133.2 (C-20,60),
131.5 (C-40), 128.8 (C-30,50), 125.6 (C-3), 121.8 (C-9),
116.1 (C-4), 111.4 (C-6), 104.5 (C-7), 55.9 (Ar–OCH3); MS
(ESI, positive scan): m/z 287 (M+H)+, 289 (M+H)+. Analysis
found: C, 67.00; H, 3.90%. Calcd for C16H11ClO3: C, 67.03;
H, 3.87%.
1
d 166.5 (C-2), 164.0 (d, JCF¼252 Hz, C-40), 154.0 (C-5),
3
146.2 (C-8), 138.2 (C-10), 134.3 (d, JCF¼9 Hz, C-20,60),
129.6 (d, 4JCF¼3 Hz, C-10), 125.6 (C-3), 121.2 (C-9), 117.1
2
(C-4), 115.5 (d, JCF¼22 Hz, C-30,50), 111.0 (C-6), 106.1
(C-7); MS (ESI, negative scan): m/z 255 (MꢀH)ꢀ. Analysis
found: C, 70.26; H, 3.58%. Calcd for C15H9FO3: C, 70.31;
H, 3.54%.
4.5.9. 3-[(4-Methoxyphenyl)methylene]-5-methyl-
benzo[b]furan-2-one (10E). Yellow powder (120 mg,
30%), mp 102–104 ꢂC; IR (neat): 1778, 1629, 1601, 1265,
1184, 1123, 1111, 1079, 1032, 968 cmꢀ1
;
1H NMR
4.5.5. 3-[(4-Chlorophenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (8E). Yellow powder (180 mg, 44%),
mp 216–218 ꢂC; IR (neat): 3387, 2922, 1740, 1610, 1209,
(CDCl3): d 2.39 (3H, s, Ar–CH3), 3.89 (3H, s, Ar–OCH3),
6.86 (1H, d, J¼7.8 Hz, H-7), 6.95 (1H, s, H-4), 7.00 (2H, d,
J¼8.7 Hz, H-30,50), 7.67 (2H, d, J¼8.7 Hz, H-20,60), 7.68
(1H, d, J¼7.8 Hz, H-6), 7.72 (1H, s, H-10); 13C NMR
(CDCl3): d 169.7 (C-2), 161.4 (C-40), 154.4 (C-8), 141.3
(C-10), 139.6 (C-10), 131.6 (C-20,60), 126.7 (C-5), 124.2
(C-6), 122.1 (C-4), 120.0 (C-3), 119.5 (C-9), 114.2
(C-30,50), 111.6 (C-7), 55.4 (Ar–OCH3), 21.9 (Ar–CH3);
MS (ESI, positive scan): m/z 267 (M+H)+. Analysis found:
C, 76.64; H, 5.36%. Calcd for C17H14O3: C, 76.68; H, 5.30%.
1115, 1010 cmꢀ1 1H NMR (CDCl3+DMSO-d6): d 6.85
;
(1H, dd, J¼8.7, 2.4 Hz, H-6), 6.95 (1H, d, J¼8.7 Hz, H-7),
7.19 (1H, d, J¼2.4 Hz, H-4), 7.48 (2H, d, J¼8.2 Hz, H-
30,50), 7.64 (2H, d, J¼8.2 Hz, H-20,60), 7.72 (1H, s, H-10),
8.94 (1H, br s, Ar–OH); 13C NMR (CDCl3+DMSO-d6):
d 169.2 (C-2), 153.7 (C-5), 147.7 (C-8), 138.4 (C-10),
135.9 (C-10), 132.4 (C-40), 130.7 (C-20,60), 129.1 (C-30,50),
123.6 (C-3), 121.6 (C-9), 118.3 (C-4), 111.5 (C-6), 109.5
(C-7); MS (ESI, negative scan): m/z 271 (MꢀH)ꢀ, 273
(MꢀH)ꢀ. Analysis found: C, 66.02; H, 3.35%. Calcd for
C15H9ClO3: C, 66.07; H, 3.33%.
4.5.10. 3-[(4-Methoxyphenyl)methylene]-5-methyl-
benzo[b]furan-2-one (10Z). Yellow powder (60 mg, 15%),
mp 122–124 ꢂC; IR (neat): 1754, 1621, 1264, 1219, 1178,
1
1043, 945 cmꢀ1; H NMR (CDCl3): d 2.40 (3H, s, Ar–
4.5.6. 3-[(4-Chlorophenyl)methylene]-5-hydroxy-
benzo[b]furan-2-one (8Z). Yellow powder (100 mg, 25%),
mp 200–202 ꢂC; IR (neat): 3345, 1760, 1600, 1192, 1047,
CH3), 3.88 (3H, s, Ar–OCH3), 6.91 (1H, s, H-4), 6.97 (2H,
d, J¼8.7 Hz, H-30,50), 6.98 (1H, dd, J¼7.7, 2.1 Hz, H-6),
7.37 (1H, d, J¼7.7 Hz, H-7), 7.48 (1H, s, H-10), 8.24 (2H,
d, J¼8.1 Hz, H-20,60); 13C NMR (CDCl3): d 166.7 (C-2),
162.1 (C-40), 152.8 (C-8), 139.8 (C-10), 139.0 (C-10), 134.4
(C-20,60), 126.5 (C-5), 124.4 (C-6), 123.2 (C-3), 118.6
1
918 cmꢀ1; H NMR (CDCl3+DMSO-d6): d 6.83 (1H, d,
J¼8.4 Hz, H-6), 6.90 (1H, d, J¼8.4 Hz, H-7), 7.02 (1H, br
s, H-4), 7.41 (2H, d, J¼8.1 Hz, H-30,50), 7.49 (1H, s, H-10),

9860
S. Venkateswarlu et al. / Tetrahedron 62 (2006) 9855–9860
(C-4), 118.2 (C-9), 114.0 (C-30,50), 111.2 (C-7), 55.4 (Ar–
OCH3), 21.9 (Ar–CH3); MS (ESI, positive scan): m/z 267
(M+H)+. Analysis found: C, 76.65; H, 5.34%. Calcd for
C17H14O3: C, 76.68; H, 5.30%.
and encouragement, and Professor A. Srikrishna, Indian
Institute of Science, Bangalore, India for helpful discussions.
References and notes
4.5.11. 5-Hydroxy-3-[(4-hydroxyphenyl)methylene]-
benzo[b]furan-2-one (11E). Yellow powder (76 mg,
20%), mp 258–260 ꢂC (lit.7 mp 245–247 ꢂC); IR (KBr):
3385, 3279, 1749, 1601, 1292, 1252, 1145, 1119 cmꢀ1; 1H
NMR (DMSO-d6): see Table 4; 13C NMR (DMSO-d6): d
169.6 (C-2), 159.8 (C-40), 153.1 (C-5), 146.7 (C-8), 140.9
(C-10), 131.7 (C-20,60), 124.5 (C-10), 122.1 (C-3), 119.1
(C-9), 116.6 (C-4), 115.6 (C-30,50), 110.6 (C-6), 108.9 (C-7);
MS (ESI, negative scan): m/z 253 (MꢀH)ꢀ.
1. Harborne, J. B. The Flavonoids; Chapman and Hall: London,
1988; pp 340–342.
2. Boumendjel, A. Curr. Med. Chem. 2003, 10, 2621–2630.
3. Thakkar, K.; Cushman, M. J. Org. Chem. 1995, 60, 6499–
6510.
4. Varma, R. S.; Varma, M. Tetrahedron Lett. 1992, 33, 5937–
5940.
5. Hastings, J. S.; Heller, H. G. J. Chem. Soc., Perkin Trans. 1
1972, 2128–2132.
4.5.12. 5-Hydroxy-3-[(4-hydroxyphenyl)methylene]-
benzo[b]furan-2-one (11Z). Yellow powder (19 mg, 5%),
mp 245–247 ꢂC; IR (KBr): 3389, 3294, 1724, 1602, 1297,
6. Pelter, A.; Ward, R. S.; Heller, H. G. J. Chem. Soc., Perkin
Trans. 1 1979, 328–329.
7. Schildknecht, H.; Kornig, W.; Siewerdt, R.; Krauss, D. Liebigs
Ann. Chem. 1970, 734, 116–125.
8. Suzuki, K.; Yahara, S.; Maehata, K.; Uyeda, M. J. Nat. Prod.
2001, 64, 204–207.
1
1211, 1180, 1115, 1081 cmꢀ1; H NMR (DMSO-d6): see
Table 4; MS (ESI, negative scan): m/z 253 (MꢀH)ꢀ.
4.5.13. 5-Hydroxy-3-[(3,4-dihydroxyphenyl)methylene]-
benzo[b]furan-2-one (12E/Z). Yellow powder (183 mg,
45%, HPLC: E/Z 79:19), mp 240–243 ꢂC; IR (KBr): 3343,
9. Qin, P.; Peiquan, Y.; Guihong, C.; Weijian, L. Zhongcaoyao
1998, 29, 76–79.
10. Handa, S. S.; Singh, R.; Maurya, R.; Satti, N. K.; Suri, K. A.;
Suri, O. P. Tetrahedron Lett. 2000, 41, 1579–1581.
11. Gray, T. I.; Pelter, A.; Ward, R. S. Tetrahedron 1979, 35, 2539–
2543.
12. Barbier, M. Liebigs Ann. Chem. 1987, 545–546.
13. Venkateswarlu, S.; Panchagnula, G. K.; Guraiah, M. B.;
Subbaraju, G. V. Tetrahedron 2005, 61, 3013–3017.
14. Suzuki, K.; Okawara, T.; Higashijima, T.; Yokomizo, K.;
Mizushima, T.; Otsuka, M. Bioorg. Med. Chem. Lett. 2005,
15, 2065–2068.
3256, 1754, 1596, 1240, 1143, 1120, 1101, 1004 cmꢀ1
;
1H NMR (DMSO-d6): d peaks correspond to E-isomer, 6.78
(1H, dd, J¼2.4, 8.4 Hz, H-6), 6.88 (1H, d, J¼8.2 Hz, H-50),
7.06 (1H, d, J¼8.4 Hz, H-7), 7.17 (1H, d, J¼8.2 Hz, H-60),
7.23 (1H, d, J¼1.8 Hz, H-20), 7.37 (1H, d, J¼2.4 Hz,
H-4), 7.62 (1H, s, H-10); 13C NMR (CDCl3+DMSO-d6):
d 169.7 (C-2), 153.1 (C-5), 148.1 (C-40), 146.8 (C-8), 144.8
(C-30), 141.4 (C-10), 125.2 (C-10), 123.2 (C-20), 122.2
(C-3), 119.0 (C-9), 116.6 (C-60), 116.4 (C-50), 115.5 (C-4),
110.6 (C-6), 109.3 (C-7); MS (ESI, negative scan): m/z 269
(MꢀH)ꢀ. Analysis found: C, 66.64; H, 3.75%. Calcd for
C15H10O5: C, 66.67; H, 3.73%.
15. Marathe, K. G.; Byrne, M. J.; Vidwans, R. N. Tetrahedron
1966, 22, 1789–1795.
16. Mujahid Alam, M.; Adapa, S. R. Synth. Commun. 2003, 33,
59–63.
4.5.14. 5-Hydroxy-3-[(3,4,5-trihydroxyphenyl)methylene]-
benzo[b]furan-2-one (13E/Z). Yellow powder (155 mg,
36%, HPLC: E/Z 80:20), mp 270–273 ꢂC; IR (KBr): 3367,
17. E1-Sayrafi, S.; Rayyan, S. Molecules 2001, 6, 279–286.
18. Ganga Raju, G.; Subbaraju, G. V.; Venkateswarlu, S. U.S.
Patent No. 6,900,356, 2005.
19. Rizzi, E.; Dallavalle, S.; Merlini, L.; Beretta, G. L.; Pratesi, G.;
Zunino, F. Bioorg. Med. Chem. Lett. 2005, 15, 4313–4316.
20. Bevan, J. A.; Gagnon, P. E.; Rae, I. D. Can. J. Chem. 1965, 43,
2612–2614.
21. Kevill, D. N.; Weiler, E. D.; Cromwell, N. H. J. Org. Chem.
1964, 29, 1276–1278.
22. McCord, J. M.; Fridovich, I. J. Biol. Chem. 1969, 244,
6049–6055.
1
1758, 1598, 1236, 1143, 1109, 1039, 990 cmꢀ1; H NMR
(DMSO-d6): d peaks correspond to E-isomer, 6.78 (2H, s,
H-20,60), 6.79 (1H, dd, J¼2.4, 8.6 Hz, H-6), 7.06 (1H, d,
J¼8.6 Hz, H-7), 7.40 (1H, d, J¼2.4 Hz, H-4), 7.55 (1H, s,
H-10), 9.12 (1H, br s, Ar–OH), 9.46 (2H, br s, 2ꢁAr–OH),
9.48 (1H, br s, Ar–OH); 13C NMR (DMSO-d6): d 169.5
(C-2), 153.6 (C-8), 146.4 (C-5), 146.1 (C-30,50), 142.5
(C-10), 137.3 (C-40), 123.7 (C-10), 122.3 (C-3), 118.4 (C-9),
116.9 (C-4), 111.3 (C-6), 109.7 (C-20,60), 109.3 (C-7); MS
(ESI, negative scan): m/z 285 (MꢀH)ꢀ. Analysis found: C,
62.91; H, 3.55%. Calcd for C15H10O6: C, 62.94; H, 3.52%.
23. Venkateswarlu, S.; Ramachandra, M. S.; Subbaraju, G. V.
Bioorg. Med. Chem. 2005, 13, 6374–6380.
24. Elliger, C. A.; Waiss jun, A. C.; Lundin, R. E. J. Chem. Soc.,
Perkin Trans. 1 1973, 2209–2212.
Acknowledgements
25. Aubert, O.; Augdahl, E.; Berner, E. Acta Chem. Scand. 1952, 6,
433–439.
We sincerely thank Sri G. Ganga Raju, Chairman, and Mr. G.
Rama Raju, Director, of Laila Impex for providing facilities
26. Holmquist, H. E. J. Org. Chem. 1969, 34, 4164–4165.
27. Bostock, S. B.; Renfrew, A. H. Synthesis 1978, 66–67.