An alternate method for the synthesis of 2-aryl/alkyl-5-bromo-7-methoxy benzofurans; application to the synthesis of Egonol, Homoegonol, and analogs via Heck reaction

Article abstract of DOI:10.1016/j.tet.2016.09.068

We herein report the general, versatile, and convenient method for the synthesis of 2-arly/alkyl-5-bromo-7-methoxy benzofurans from easily available o-Vanillin in five steps. These benzofurans was successfully converted into biological active natural products Egonol, Homoegonol, and analogous on applying Heck reaction using ethyl/methyl acrylate in the presence of palladium catalyst.

Full text of DOI:10.1016/j.tet.2016.09.068

Accepted Manuscript
An alternate method for the synthesis of 2-aryl/alkyl-5-bromo-7-methoxy benzofurans;
application to the synthesis of Egonol, Homoegonol and analogs via Heck reaction
Kishor R. More, R.S. Mali
PII:
S0040-4020(16)30999-1
10.1016/j.tet.2016.09.068
TET 28139
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 June 2016
Revised Date: 27 September 2016
Accepted Date: 29 September 2016
Please cite this article as: More KR, Mali RS, An alternate method for the synthesis of 2-aryl/alkyl-5-
bromo-7-methoxy benzofurans; application to the synthesis of Egonol, Homoegonol and analogs via
Heck reaction, Tetrahedron (2016), doi: 10.1016/j.tet.2016.09.068.
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ACCEPTED MANUSCRIPT
Graphical Abstract
An alternate method for the synthesis of 2-aryl/alkyl-5-
bromo-7-methoxy benzofurans; Application to the
synthesis of Egonol, Homoegonol and Analogs via Heck reaction
Kishor R. More*, R. S. Mali
Garware Research Centre, Department of Chemistry, Pune University, Pune, 411007, India
1

ACCEPTED MANUSCRIPT
An alternate method for the synthesis of 2-aryl/alkyl-5-bromo-7-methoxy benzofurans;
Application to the synthesis of Egonol, Homoegonol and Analogs via Heck reaction
Kishor R. More*, R. S. Mali
Garware Research Centre, Department of Chemistry, University Of Pune,
Pune, 411007, India
*Corresponding email address: kishor.more@ipca.com
Telephone: +912261112720, Fax: 62105005
2

ACCEPTED MANUSCRIPT
Abstract:
We herein report the general, versatile and convenient method for the synthesis of 2-arly/alkyl-5-bromo-
7-methoxy benzofurans from easily available o-Vanillin in five steps. These benzofurans was
successfully converted into biological active natural products Egonol, Homoegonol and analogous on
applying Heck reaction using ethyl/methyl acrylate in the presence of palladium catalyst.
Key Words:
2-aryl/alkyl-5-bromo-7-methoxy benzofurans
Egonol
Homoegonol
Heck reaction
Synthesis
3

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1. Introduction
2-aryl/alkylbenzofurans constitute an important subclass of naturally occurring Lignans
and Neolignans. These compounds have attracted much attention in medicinal chemistry for their
remarkable and diverse biological activities.1-4 Egonol (I) and Homoegonol (II) are among the
most recognized benzofurans which possess hydroxypropyl side chain at C-5 position. They
have isolated from the Styracaceae family such as S. japonicum, S. formosanus, S. Obassia, S.
macranthus, and S. officinalis.5, 6 Egonoic acid (III), an acid analog of Egonol was isolated from
the wood of Anaxagorea clavata.7 These compounds were found to exhibit broad range of
biological activities including cytotoxicity, antimicrobial, fungicidal, anti-inflammatory, anti-
asthama and anti-oxidant properties.8-11 Lignans like (IV) possess formyl group at C-3 position
along with the 3-hydroxypropyl side chain at C-5 position has also been reported for its
adenosine A1 receptor activities.12
In view of this broad spectrum of biological activity and therapeutic applications
associated with these compounds, number of approaches has been developed for the efficient
synthesis of their basic skeleton.13 Several methods have been reported for the synthesis of 2-
aryl/alkyl-5-carboxyaldehyde/allyl benzofurans and their usefulness in the preparation of above
bioactive natural products. Many researchers have employed conventional coupling reactions for
the synthesis of such compounds.14 Major drawbacks of those approaches are complexity and
low yield. In designing an alternate and simple synthesis of Egonol, Homoegonol and analogous
compounds we decided to use Heck reaction as this reaction is well known to generate vinylic
compounds from the aromatic halides.15 To achieve the desired synthetic application of Heck
reaction in the preparation of Egonol and analogous, we first developed a general, versatile and
convenient method for the synthesis of 2-aryl/alkyl-5-bromo benzofurans (A) from easily
available o-Vanillin in five steps. Heck reaction was performed on these benzofurans using
ethyl/methyl acrylate in the presence of palladium catalyst to afford 5-(2-
(ethoxy/methoxycarbonyl)-E-ethenyl)-7-methoxy benzofurans (B) which on reduction with
lithium aluminium hydride successfully produced (I) and (II). We herein report for the first time
the synthesis of 2-arly/alkyl-5-bromo-7-methoxy benzofurans and their application in the
synthesis of Egonol, Homoegonol and analogous via Heck reaction (Fig. 1).
4

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2. Results and Discussions
Synthesis of 2-arly/alkyl-5-bromo-7-methoxy benzofurans was carried from o-Vanillin as
described in Scheme-1. 5-Bromo-o-vanillin 1 was synthesized by doing bromination on vanillin
using bromine in ethylene dichloride as per reported literature.16 Conversion of 5-bromo-o-
vanillin into benzyl alcohol 2 was achieved using sodium borohydride in THF at 0 °C in 82%
yield. The completion of reaction was confirmed by doing 2,4-DNP test. After 2 h, the negative
2, 4-DNP test indicates the absence of formyl group, hence completion of the reaction. To
improve the yield we tried the solvent monoglyme under same reaction conditions and
successfully obtained 2 in 94% yield. This benzyl alcohol was then reacted with thionyl chloride
in dry MDC to afford 2-hydroxy-3-methoxy-5-bromobenzylchloride 3 as a brown solid. In IR
(KBr) spectrum presence of band at 3491cm-1 confirmed the presence of OH group. The next
step was the formation of phosphonium salt 4 by the reaction of 3 with triphenylphosphine in dry
benzene under refluxing condition for 5 h. The soild separated out was filtered, washed with
benzene and dried to afford phosphonium salt 4, m.p. 244-245 °C (decomp.). It exhibited an
affirmative FeCl3 test and in IR (KBr) spectrum, band at 3428 cm-1 confirmed the presence of
phenolic-OH group. These phosphonium salts on reaction with different benzoyl chloride
(Scheme 1a) and methyl/formyl chloride (Scheme 1b) in toluene under reflux conditions in the
presence of base triethylamine afforded corresponding 2-arly/alkyl-5-bromo-7-methoxy
benzofurans (6-14) in good to moderate yield.
5

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Preparation of 5-(2-(ethoxy/methoxycarbonyl)-E-ethenyl)-7-methoxy-2-arylbenzofurans from 2-
arly-5-bromo-7-methoxy benzofurans have been carried out as described in Scheme 2. The main
challenge in the projected synthesis was the formation of α, β unsaturated esters (15a-22b) from
these 5-bromobenzofurans. This was overcome by the application of Heck reaction. Reaction
conditions were optimized and the best results achieved when mixture of 5-bromobenzofurans 6-
12, (1 mmol), ethyl acrylate (2 mmol), triphenylphoshine (0.2 mmol), potassium carbonate (2
mmol) and palladium acetate (0.1 mmol) was heated under reflux for 6 h in the solvent
acetonitrile under argon atmosphere. Yield of corresponding 5-(2-(ethoxycarbonyl)-E-ethenyl)-
benzofurans (15a-22b) obtained was around 65-70% yield.
6

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Scheme 2:
Br
O
R3
R2
O
OR4
R4O
a
OMe
R3
R2
R
O
O
R1
OMe
Acrylates
R
R1
(V) R4= Ethyl
6) R=R1=R2=R3=H
7) R=H, R1=R2=R3=OMe
(VI
) R4= Methyl
15a)
R4= Et, R=R=R2=R3=H
16a) R4=Et, R=H, R1=R2=R3=OMe
17a) R4=Et, R=R3=H, R1-R2=-OCH2O-
18a)
10)
R=R3=H, R1-R2=-OCH2O-
11) R=R3=H, R1=R2=OMe
12)
R=R3=H, R1=OMe, R2=OCh2Ph
R4=Et, R=R3=H, R1=R2=OMe
19a) R4=Et, R=R3=H, R1=OMe, R2=OCH2Ph
20b)
21b)
R4=Me, R=R3=H, R1-R2=-OCH2O-
R4=Me, R=R3=H, R1=R2=OMe
22b) R4=Me, R=R3=H, R1=OMe, R2=OCH2Ph
Reagents and Conditions
: a) PPh3, K2CO3, Pd(OAc)2, ACN, 80 C, (65-85%)
Last section of our proposed synthesis was the conversion of above obtained 5-(2-
(ethoxycarbonyl)-E-ethenyl)-benzofurans (15a-22b) into the required natural products and
analogs. Egonol (I) and Homoegonol (II) was successfully achieved by the conversion of
corresponding α, β unsaturated esters (16a, 17a, 18a, 20b) into alcohols via reduction with
lithium aluminium hydride (LAH) in THF (Scheme 3). 3 moles of LAH have been used for
complete reduction of unsaturated esters into alcohols. Initial the addition was done at 0 °C and
then reaction was continued at room temperature for 4-5 h. All these, β unsaturated esters was
successfully converted into required products in around 70% yield.
Till date only one method has been reported for the conversion of Egonol into Egonoic acid (III)
which involves the oxidation with chromium oxide in pyridine.17 We have developed a simple
two step synthesis starting from 5-(2-(ethoxy/methoxycarbonyl)-E-ethenyl)-7-methoxy-2-(3,4-
7

ACCEPTED MANUSCRIPT
dimethoxyphenyl) benzofuran (Scheme 4). First step is the conversion of α, β unsaturated esters
(16a-19a and 20b-22b) into dihydroesters (24-31) in the presence of 5% Pd/C in THF at room
temperature. Then these dihydroesters were hydrolyzed in the presence of NaOH and methanol
to give corresponding acids (32-34). Compound 19a and 22b reacts with 5% Pd/C in THF at
hydrogen pressure of 44 psi and results into the formation of corresponding dihydroester (27 &
30). While on increasing the pressure to 60 psi it gets converted into dihydroester (28 & 31)
along with the removal of O-benzyl group.
Scheme 4:
O
O
O
R4O
R3
R2
HO
R4O
O
R3
R2
R3
R2
OMe
O
a
O
b
R
OMe
OMe
R1
R
R
R1
R1
16a) R4=Et, R=H, R1=R2=R3=OMe
17a) R4=Et, R=R3=H, R1=R2=-OCH2O-
18a) R4=Et, R=R3=H, R1=R2=-OMe
19a) R4=Et, R=R3=H, R1=OMe, R2=-OCH2Ph
20b) R4=Me, R=R3=H, R1-R2=-OCH2O-
21b) R4=Me, R=R3=H, R1=R2=-OMe
24) R4=Et, R=H, R1=R2=R3=OMe
25) R4=Et, R=R3=H, R1=R2=-OCH2O-
26) R4=Et, R=R3=H, R1=R2=-OMe
27) R4=Et, R=R3=H, R1=OMe, R2=-OCH2Ph, p=44 psi
28) R4= Et, R=R3=H, R1=OMe, R2=OH,p=60 psi
29) R4=Me, R=R3=H, R1=R2=-OMe
30) R4=Me, R=R3=H, R1=OMe, R2=-OCH2Ph
31) R4=Me, R=R3=H, R1=OMe, R2=OH
33)R=H, R1=R2=R3=OMe
Egonoic acid (III), R=R3=H,
R1-R2=-OCH2O-
34) R=R3=H, R1=R2=OMe
35) R=R3=H, R1=OMe, R2=OH
22b) R4=Me, R=R3=H, R1=OMe, R2=-OCH2Ph
32) R4=Me, R=R3=H, R1-R2=-OCH2O-
Reagents and Conditions: a) 5% Pd/C, THF, rt, (65ꢀ85%); b) 1N NaOH, MeOH, 60 °C, 1N HCl, (60ꢀ90%)
As described in Scheme 5, compound 28 and 31 react with lithium aluminium hydride (2.8
mmol) in THF at 0 °C to give alcohol (32) in ~80% yield. The C-3 formylation of its acetylated
derivative using Gatterman reaction have already been reported in literature.18, 19 In this way we
successfully achieved the formal synthesis of Lignans (IV).
3. Conclusions
We have devised an efficient method for the synthesis of 5-bromo-7-methoxy-2-aryl-/2-
alkylbenzofurans from easily available o-vanillin and their application in the synthesis of
Egonol, Homoegonol and related compounds using Heck reaction.
8

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4. Experimental
4.1 General
All melting points recorded are uncorrected and are measured in degree Celsius with a
Thomas Hoover Capillary melting point apparatus. NMR spectra were recorded on Joel FX
90Q (90 MHz) and Varian Mercury 300 (300 MHz) spectrometers using tetramethylsilane
(TMS) as an internal standard. IR spectra were recorded on FT IR-Perkin Elmer 1600
instrument. Elemental analysis was obtained using Hoslis’s and Perkin Elmer 2400 carbon-
hydrogen analyzer. All studies were done at Department of Chemistry, University of Pune.
4.2 2-hydroxy-3-methoxy-5-bromobenzaldehyde (1)
To a well stirred mixture of o-vanillin (20 g, 130 mmol) in dichloroethane (75 mL),
liquid bromine (23.2 g, 140 mmol) was added over a period of 0.5 hr., at room temperature.
The reaction was completed in 1 hr. (monitored by TLC). Ice cold water (50 mL) was added
to the reaction mixture. The organic layer was separated and washed with water. It was dried
over anhydrous Na2SO4. Dichloroethane was removed under reduced pressure to give a crude
solid product. Which was recrystallized from dichloromethane: methanol (1:1) to give a pure
5-bromo-o-vanilin 5 (25 g, 82%), m.p. 132-32 °C, (lit. 16 127-29 °C).
4.3 Preparation of 2-hydroxy-3-methoxy-5-bromobenzyl alcohol (2)
Sodium borohydride (0.83 g, 20 mmol) was added in lots to a well cooled solution of 5-
bromo-o-vanillin 1 (10 g, 43 mmol) in monoglyme (60 mL). The reaction mixture was stirred
at 0 °C for 15 min and decomposed with ice cold water (25 mL). The mixture was saturated
with sodium chloride and extracted with dichloromethane (2 × 50 mL). The organic layer
was washed with water and dried over anhydrous Na2SO4. Evaporation of solvent gave a
crude solid product, which was recrystallized from hexane to furnish benzylalcohol 2 (9.5 g,
94%), m.p. 90-91 °C (lit.20 91-92 °C). 1HNMR (400 MHz, CDCl3) δ 7.04(d, J= 1.8Hz, 1H),
6.94(d, J= 1.8Hz, 1H), 4.71(s, 2H, CH2OH), 3.89(s, 3H, OCH3) 1.76(bs, 2H, OH); 13C NMR
(100 MHz, CDCl3) δ150.2, 145.6, 128.0, 131.2, 119.5, 108.9, 59.0, 54.2.
4.4 Preparation of 2-hydroxy-3-methoxy-5-bromobenzyl chloride (3)
Thionyl chloride (2.0 g, 17 mmol) was added dropwise to a well stirred solution of
°
benzyl alcohol 2 (2.0 g, 8.6 mmol) in dry dichloromethane (60 mL) at 0 C. The reaction
mixture was stirred at 0 °C for 1 hr. (monitored by TLC). Ice cold water (50 mL) was added,
separated the organic layer and aqueous layer was extracted with dichloromethane (2 × 10
mL). The combined organic layer was washed with water and dried (Na2SO4). The solvent
was evaporated to give a solid which on crystallization from dichloromethane: hexane (2: 8)
1
afforded 7 (2 g, 93%) as a brown colour solid m.p. 73-75 °C. HNMR (400 MHz, CDCl3) δ
7.10(bs, 1H), 6.94(bs, 1H), 5.82(s, 1H, OH), 4.61(s, 2H, CH2Cl), 3.89(s, 3H, OCH3); 13C
NMR (100 MHz, CDCl3) δ 151.5, 146.0, 117.0, 134.2, 121.5, 106.5, 55.7, 51.3.
4.5 Preparation of 2-hydroxy-3-methoxy-5-bromobenzyltriphenyl-phosphonium chloride
(4)
9

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Dry benzene (50 mL) was added to a mixture of triphenylphosphine (2.5 g, 9.4 mmol)
and benzyl chloride 3 (2.0 g, 7.6 mmol) and the reaction mixture was refluxed for 5 h. The
solid product separated out was filtered, washed with warm benzene and dried to furnish the
phosphonium salt 4 (3.5 g, 88%) as a white crystalline solid, m.p. 244-45 °C (decomp.).
4.6 Preparation of 5-bromo-7methoxy-2-phenylbenzofuran (6)
A solution of benzoic acid (0.30 g, 2.4 mmol) and thionyl chloride (0.43 g, 3.6 mmol) in
toluene (10 mL) was heated under reflux for 4 hr. Excess of toluene and thionyl chloride was
removed under reduced pressure to furnish benzoyl chloride (0.19 g) which was used further
without purification. A mixture of phosphonium salt 4 (0.2 g, 0.39 mmol), benzoyl chloride
(0.065 g, 0.46 mmol) and triethylamine (0.09 g, 0.89 mmol) in toluene (30 mL) was heated
under reflux for 6 hr. The reaction mixture was allowed to cool to room temperature. Water
(25 mL) was added to it. The organic layer was separated, washed with water (25 mL × 2)
and dried (Na2SO4). Toluene from the organic layer layer was distilled off under reduced
pressure to give a gummy mass which was purified by passing it through a column of silica
gel using ethyl acetate: hexane (1:9) as an eluent. The initial fraction on evaporation gave a
solid which on recrystallization from dichloromethane: hexane (8:2) furnished the 5-
bromobenzofuran 6 (0.075 g, 64%) as a white solid m.p. 115-116 °C. [Found: C, 59.98; H,
1
3.40. C15H11BrO2 requires C, 59.59; H, 3.65%]; HNMR (400 MHz, CDCl3) δ 7.86-7.88(m,
2H, Ar-H), 7.36-7.48(m, 3H, Ar-H), 7.32(d, J= 1.2Hz, 1H), 6.95(s, 1H), 6.91(d, J= 1.2Hz,
13
1H), 4.04(s, 3H, OCH3); C NMR (100 MHz, CDCl3) δ 155.0, 145.6, 143.3, 125.0, 124.2,
119.7, 117.3, 114.2, 115.0, 109.6, 109.1, 108.0, 107.8, 99.8, 55.6; IR(cm-1,KBr): 1616, 1586,
1493, 1472, 1247, 1154.
4.7 General procedure for preparation of 5-bromo-7-methoxy-2arylbenzofurans (7-12)
A solution of substituted benzoic acids (1 mmol) in thionyl chloride (1.5 mmol) in
toluene was heated under reflux for 4 hr. Excess of toluene and thionyl chloride was removed
under reduced pressure to furnish benzoyl chlorides which were used further without
purification.
A mixture of phosphonium salt 4 (1 mmol), benzoyl chlorides (1.1 mmol) and triethylamine
(2.3 mmol) in toluene was heated under reflux for 3-6 h. Once the reaction completed, usual
work up was done as mentioned above. Solid products obtained were purified through silica
gel column using hexane: ethyl acetate (9.5: 0.5) as an eluent to give the desired derivatives
(7-12) in 60-70% yield range.
4.7.1 5-bromo-7-methoxy-2-(3,4,5-trimethoxyphenyl)benzofuran (7)
White solid, Yield 59%; m.p. 187-188 °C; Rf (5% EtOAc/hexane) 0.45; [Found: C, 54.80; H,
1
4.10. C18H17BrO5 requires C, 54.98; H, 4.35%]; HNMR (400 MHz, CDCl3) δ 7.33(bs, 1H),
7.28(s, 2H, Ar-H), 6.93(bs, 1H), 6.90(s, 1H), 4.05(s, 3H, OCH3), 3.98(s, 6H, 2-OCH3),
13
3.92(s, 3H, OCH3); C NMR (100 MHz, CDCl3) δ 156.8, 149, 147.3, 145.5, 144.0, 142.9,
131, 126.9, 124, 117.3, 114.6, 102, 56.7, 56.5, 55, 53.2 ; IR(cm-1,KBr): 1589, 1507, 1472,
1243, 1131.
10

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4.7.2 5-bromo-7-methoxy-2-(4-methoxyphenyl)benzofuran (8)
White crystalline solid, Yield 66%; m.p. 130-131 °C; Rf (5% EtOAc/hexane) 0.65; [Found:
1
C, 57.70; H, 4.00. C16H13BrO3 requires C, 57.67; H, 3.93%]; HNMR (400 MHz, CDCl3) δ
7.79(d, J=8.7Hz, 2H), 7.29(d, J= 1.8Hz, 1H), 6.97(d, J= 8.7Hz, 2H), 6.88(d, J=1.8Hz, 1H),
6.80(s, 1H), 4.02(s, 3H, OCH3), 3.86(s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 156,
151.6, 149, 143.4, 128.9, 128, 127.5, 118, 114.1, 111, 108, 105.7, 101.3, 54.5, 51.8; IR(cm-
1,KBr): 1612, 1505, 1472, 1254, 1174.
4.6.3 5-bromo-7-methoxy-2-(2-chlorophenyl)benzofuran (9)
White solid, Yield 65%; m.p. 105-106 °C; Rf (5% EtOAc/hexane) 0.71; [Found: C, 53.60; H,
1
2.69. C15H10BrClO2 requires C, 53.36; H, 2.98%]; HNMR (400 MHz, CDCl3) δ 8.06(bs,
1H), 7.51(d, J=1.8Hz, 1H), 7.48(d, J=1.8Hz, 1H), 7.35(m, 1H), 7.31(m, 1H), 7.26(bs, 1H),
6.94(s, 1H), 4.03(s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 154, 152.5, 141, 139.6,
127.7, 127, 126.3, 116, 111.8, 109, 105.6, 105, 99.8, 56; IR(cm-1,KBr): 1588, 1481, 1469,
1250, 1185.
4.6.4 5-bromo-7-methoxy-2-(3,4,-methylenedioxyphenyl)benzofuran (10)
White solid, Yield 53%; m.p. 167-169 °C; Rf (5% EtOAc/hexane) 0.55; [Found: C, 55.50; H,
1
3.42. C16H11BrO4 requires C, 55.35; H, 3.19%]; HNMR (400 MHz, CDCl3) δ 7.43(dd, J=
8.1Hz, J= 1.84Hz), 7.31(d, J=1.8Hz, 1H), 7.29(d, J=1.2Hz, 1H), 6.89(d, J= 1.2Hz, 1H),
6.86(d, J= 8.1Hz, 1H), 6.79(s, 1H), 6.02(s, 2H), 4.02(s, 3H); 13C NMR (100 MHz, CDCl3,
DMSO-d6) δ 153, 143.6, 142, 140.9, 131.4, 124.5, 124, 122.2, 119.7, 111.3, 104.6, 107,
102.4, 55.4; IR(cm-1,KBr):1585, 1501, 1476, 1248, 1169.
4.6.5 5-bromo-7-methoxy-2-(3,4-dimethoxyphenyl)benzofuran (11)
White solid, Yield 53%; m.p. 201-202 °C; Rf (5% EtOAc/hexane) 0.61; [Found: C, 56.20; H,
1
3.90. C17H15BrO4 requires C, 56.20; H, 4.16%]; HNMR (400 MHz, CDCl3) δ 7.47(dd, J=
8.1Hz,1.8Hz, 1H), 7.37(d, J=1.8Hz), 7.31(d, J=1.2Hz, 1H), 6.95(d, J=8.1Hz, 1H), 6.91(d,
13
J=1.2Hz, 1H), 6.83(s, 1H), 4.05(s, 3H, OCH3), 4.01(s, 3H, OCH3), 3.96(s, 3H, OCH3); C
NMR (100 MHz, CDCl3) δ 151, 150.7, 149, 139, 127.1, 124.5, 123, 115, 109.7, 108, 106.3,
104.5, 55.8, 56.3, 56.8; IR(cm-1,KBr): 1584, 1511, 1470, 1125, 1137.
4.6.6 5-bromo-7-methoxy-2-(3-methoxy-4-benzyloxyphenyl)benzofuran (12)
White solid, Yield 67%; m.p. 156-158 °C; Rf (5% EtOAc/hexane) 0.42; 1HNMR (400 MHz,
CDCl3) δ 7.45(d, J=8.1Hz, 1H), 7.4-7.3(m, 6H), 6.97(bs, 1H), 6.93(d, J= 8.1Hz, 1H), 6.82(s,
1H), 6.63(bs, 1H), 5.20(s, 2H), 4.02(s, 3H), 3.99(s, 3H); 13C NMR (100 MHz, CDCl3) δ 152,
151.7, 150, 142, 141.2, 137, 129, 124, 122.5, 116, 109.7, 109, 108.6, 105.7, 104, 103.2,
101.5, 71.3, 56.7, 55.5; IR(cm-1,KBr): 1580, 1507, 1475, 1120, 1131.
4.7 Preparation of 5-bromo-7-methoxybenzofuran (13)
11

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A solution of formic acid (0.5 g, 10 mmol) and thionyl chloride (1.3 g, 1.1 mmol) in
toluene (10 mL) was stirred at room temperature for 8 h. Phosphonium salt 4 (4.5 g, 0.009
mol), triethylamine (2.5 g, 210 mmol) and toluene (100 mL) were added to it and refluxed
for 5 h. On usual workup as mentioned above, a gummy mass was obtained which was
chromatographed on a silica gel using hexane: ethyl acetate (9:1) as an eluent to afford 13 as
yellow oil (0.8 g, 40%). [Found: C, 47.40; H, 3.05. C9H7BrO2 requires C, 47.61; H, 3.11%];
1
Rf (10% EtOAc/hexane) 0.56; HNMR (400 MHz, CDCl3) δ 7.61(d, J=1.8Hz, 1H), 7.34(d,
J=1.8Hz, 1H), 6.91(d, J=1.8Hz, 1H), 6.71(d, J=1.8Hz, 1H), 3.99(s, 3H); 13C NMR (100
MHz, CDCl3) δ 154.6, 147, 142.4, 133, 126.3, 123.1, 115, 106, 57; IR(cm-1,KBr): 1590,
1500, 1475, 1130
4.8 Preparation of 5-bromo-7-methoxy-2-methylbenzofuran (14)
A mixture of phosphonium salt 4 (0.5 g, 0.97 mmol), acetyl chloride (0.9 g, 1.14 mmol)
and triethylamine in toluene (20 mL) was refluxed for 3 h. On usual workup as mentioned
above, a thick liquid was obtained which was chromatographed on a silica gel using hexane
as an eluent to furnish 14 as yellow oil (0.19 g, 81%). Rf (100% hexane) 0.74; [Found: C,
1
49.48; H, 3.91. C10H9BrO2 requires C, 49.82; H, 3.76%]; HNMR (400 MHz, CDCl3) δ
7.21(d, J=1.8Hz, 1H), 6.84(d, J=1.8Hz, 1H), 6.31(s, 1H), 3.98(s, 3H), 2.46(s, 3H); 13C NMR
(100 MHz, CDCl3) δ 157, 155.5, 141, 133.4, 126.8, 122.9, 117.3, 113, 54.3, 14.6; IR(cm-1
,KBr): 1629, 1475, 1436, 1207, 1116.
4.9 Preparation of 5-(2-(ethoxycarbonyl)
methylenedioxyphenyl) benzofuran (17a)
–
E
–ethenyl)-7-methoxy-2-(3, 4-
A mixture of 5-bromobenzofuran 10 (0.05 g 0.144 mmol), ethyl acrylate (0.028 g, 0.28
mmol), triphenylphodphine (0.075 g, 0.29 mmol), potassium carbonate (0.04 g, 0.29 mmol)
and palladium acetate (0.003 g) in acetonitrile (5 mL) was heated under reflux for 6 hr. in
argon atmosphere (monitored by TLC). The reaction mixture was cooled to room
temperature and filtered. The solvent from the filtrate was recovered under reduced pressure
to give a solid product which was chromatographed over silica gel using hexane: ethyl
acetate (9.5:0.5) as an eluent to give (E)-ethyl cinnamate 17a as white solid (0.033 g, 63%)
m.p. 170-171 °C. [Found: C, 68.90; H, 4.89. C21H18O6 requires C, 68.84; H, 4.95%]; Rf (5%
1
EtOAc/hexane) 0.35; HNMR (400 MHz, CDCl3) δ 7.78(d, J=16Hz, 1H), 7.42(d, J= 1.2Hz,
1H), 7.4(d, J=1.2Hz, 1H), 7.33(d, J=1.2Hz, 1H), 6.88(bd, J=7.8Hz, 1H), 6.86(d, J=7.8Hz,
1H), 6.85(s, 1H), 6.41(d, J=16Hz, 1H), 6.02(s, 2H, OCH2O), 4.28(q, J= 6.5Hz, 2H,
OCH2CH3), 4.06(s, 3H, OCH3), 1.35(t, J=6.5Hz, 3H, OCH2CH3); 13C NMR (100 MHz,
CDCl3) δ 167, 158.3, 149.7, 148, 147.3, 144, 142.5, 121.8, 120, 116.5, 115.1, 112.5, 105,
103.7, 98.9, 61.2, 57, 14.8; IR(cm-1, KBr): 1703, 1580, 1500, 1465, 1156.
4.10 General procedure for preparation of 5-(2-(ethoxycarbonyl) – E –ethenyl)-7-
methoxy-2-arylbenzofuran (15a-22b)
12

ACCEPTED MANUSCRIPT
A mixture of 5-bromobenzofurans 6-12, (1 mmol), ethyl acrylate (2 mmol),
triphenylphodphine (0.2 mmol), potassium carbonate (2 mmol) and palladium acetate (0.1
mmol) in acetonitrile was heated under reflux for 6 h. in argon atmosphere (monitored by
TLC). The reaction mixture was cooled to room temperature and filtered. The solvent from
the filtrate was recovered under reduced pressure to give a crude product which was
chromatographed over silica gel using hexane: ethyl acetate (9:1) as an eluent to furnish
corresponding α, β unsaturated esters.
4.10.1 5-(2-(ethoxycarbonyl) – E –ethenyl)-7-methoxy-2-phenylbenzofuran (15a)
Yield 73%, m.p. 165-166 °C. [Found: C, 74.46; H, 5.58. C20H18O4 requires C, 74.52; H,
1
5.63%]; Rf (10% EtOAc/hexane) 0.38; HNMR (400 MHz, CDCl3) δ 7.88(m, 2H), 7.76(d,
J= 15.9Hz, 1H, CH=CHCO), 7.38-7.5(m, 3H), 7.35(d, J= 1.2Hz, 1H), 7.01(s, 1H), 6.98(d,
J=1.2Hz, 1H), 6.42(d, J=15.9Hz, 1H, CH=CHCO), 4.28(q, J= 7.2Hz, 2H, OCH2CH3), 4.07(s,
3H, OCH3), 1.35(t, J=7.2Hz, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3) δ 166, 157.9,
145, 144.7, 144.1, 121.3, 120.2, 116, 113.8, 112.7, 112.3, 109, 103.6, 103, 60.6, 56, 14.3;
IR(cm-1,KBr): 1715, 1576, 1502, 1457, 1140.
4.10.2
5-(2-(ethoxycarbonyl)
–
E
–ethenyl)-7-methoxy-2-(3,4,5-
trimethoxyphenyl)benzofuran (16a)
Yield 72.5%, m.p. 140-142 °C. [Found: C, 67.10; H, 5.90. C23H24O7 requires C, 66.98; H,
5.86%]; Rf (10% EtOAc/hexane) 0.32; 1HNMR (400 MHz, CDCl3) δ 7.76(d, J= 15.9Hz, 1H,
CH=CHCO), 7.34(d, J= 1.2Hz, 1H), 7.09(s, 2H), 6.99(d, J=1.2Hz, 1H), 6.96(s, 1H), 6.42(d,
J=15.9Hz, 1H, CH=CHCO), 4.28(q, J= 7.2Hz, 2H, OCH2CH3), 4.07(s, 3H, OCH3), 3.97(s,
6H, 2-OCH3), 3.9(s, 3H, OCH3), 1.34(t, J=7.2Hz, 3H, OCH2CH3); 13C NMR (100 MHz,
CDCl3) δ 166, 157.9, 151, 149.3, 145.7, 145, 144.7, 144.1, 121.3, 120.2, 116, 113.8, 112.7,
112.3, 105.7, 59.1, 55.4, 56.8, 56.4, 56, 14.8; IR(cm-1, KBr): 1718, 1570, 1500, 1455, 1166.
4.10.3 5-(2-(ethoxycarbonyl)
–
E
–ethenyl)-7-methoxy-2-(3,4,
dimethoxyphenyl)benzofuran (18a)
Yield 72.5%, m.p. 140-142 °C. [Found: C, 68.96; H, 5.39. C22H22O6 requires C, 69.10; H,
1
5.79%]; Rf (10% EtOAc/hexane) 0.33; HNMR (400 MHz, CDCl3) δ 7.77(d, J= 15.9Hz, 1H,
CH=CHCO), 7.48(dd, J= 8.4Hz, 2.0Hz, 1H), 7.37(d, J=2.0Hz, 1H), 7.34(d, J=1.8Hz, 1H),
6.98(d, J=1.8Hz, 1H), 6.95(d, J=8.4Hz, 1H), 6.91(s, 1H), 6.43(d, J= 15.9Hz, 1H,
CH=CHCO), 4.29(q, J= 6.9Hz, 2H, OCH2CH3), 4.08(s, 3H, OCH3), 4(s, 3H, OCH3), 3.95(s,
13
3H, OCH3), 1.37(t, J=6.9Hz, 3H, OCH2CH3); C NMR (100 MHz, CDCl3) δ 165.8, 157.8,
151.3, 150.8, 144.2, 144, 132.5, 131.7, 122.4, 119, 116.5, 114.3, 112.5, 112.1, 112, 109.6,
105, 104.6, 58.8, 55.5, 56.1, 56, 18.2; IR(cm-1, KBr): 1710, 1580, 1507, 1450, 1160.
4.10.4 5-(2-(ethoxycarbonyl)–E–ethenyl)-7-methoxy-2-(3-methoxy-4-
benzyloxyphenyl)benzofuran (19a)
13

ACCEPTED MANUSCRIPT
Yield 87%, m.p. 117-119 °C. [Found: C, 73.45; H, 5.75. C28H26O6 requires C, 73.34; H,
5.71%]; Rf (10% EtOAc/hexane) 0.30; 1HNMR (400 MHz, CDCl3) δ 7.76(d, J=15.9Hz, 1H,
CH=CHCO), 7.3-7.5(m, 7H), 6.96(s, 1H), 6.93(m, 2H), 6.88(s, 1H), 6.42(d, J=15.9Hz, 1H,
CH=CHCO), 5.21(s, 2H, OCH2Ph), 4.28(q, J=6.9Hz, 2H, OCH2CH3), 4.07(s, 3H, OCH3),
13
4.00(s, 3H, OCH3), 1.36(t, J=6.9Hz, 3H, OCH2CH3); C NMR (100 MHz, CDCl3) δ 166,
155.6, 153, 147.2, 145.3, 144.9, 143, 121.3, 120, 116.4, 112.5, 112.4, 112, 110.3, 109.6,
109.2, 105, 103.8, 75, 60, 55.5, 56.1, 15; IR(cm-1,KBr): 1716, 1589, 1506, 1450, 1159.
4.10.5 5-(2-(methoxycarbonyl)–E–ethenyl)-7-methoxy-2-(3,4-
methylenedioxyphenyl)benzofuran (20b)
Yield 61%, m.p. 184-185 °C. [Found: C, 66.80; H, 4.43. C20H16O6 requires C, 68.17; H,
1
4.58%]; Rf (10% EtOAc/hexane) 0.34; HNMR (400 MHz, CDCl3) δ 7.76(d, J=16Hz, 1H),
7.42(d, J=7.5 Hz, 1.2Hz, 1H), 7.32(bs, 1H), 6.96(bs, 1H), 6.88(d, J=7.5Hz, 1H), 6.85(bs,
2H), 6.41(d, J= 16Hz, 1H, COCH=CH), 6.02(s, 2H, OCH2O), 4.06(s, 3H, OCH3), 3.82(s,
13
3H, OCH3); C NMR (100 MHz, CDCl3) δ 166.5, 158, 148.7, 148, 147.1, 143, 142.8, 121,
120.1, 115.8, 115, 112.4, 103, 1023, 97.5, 60.8, 53; IR(cm-1, KBr): 1724, 1585, 1500, 1458,
1169.
4.10.6 5-(2-(methoxycarbonyl)–E–ethenyl)-7-methoxy-2-(3,4-
dimethoxyphenyl)benzofuran (21b)
Yield 57%, m.p. 172-173 °C. [Found: C, 68.60; H, 5.50. C21H20O6 requires C, 68.47; H,
1
5.47%]; Rf (10% EtOAc/hexane) 0.36; HNMR (400 MHz, CDCl3) δ 7.80(d, J=16Hz, 1H,
CH=CHCO), 7.67(d, J=1.5Hz, 1H), 7.64(d, J=1.5Hz, 1H), 7.36(d, J=8.4Hz, 1H), 7.32(d,
J=8.4Hz, 1H), 7.28(bs, 1H), 7.26(s, 1H), 6.43(d, J=16Hz, 1H, CH=CHCO), 4.07(s, 3H,
OCH3), 3.99(s, 3H, OCH3), 3.94(s, 3H, OCH3), 3.82(s, 3H, OCH3); δ 168.9, 150, 148.7,
146.5, 144, 142.1, 140, 133.3, 121.7, 118, 117.3, 115.9, 112, 111.3, 109.2, 105, 56.5, 56,
54.3, 51.7; IR(cm-1, KBr): 1720, 1582, 1515, 1459, 1155.
4.10.7 5-(2-(methoxycarbonyl)–E–ethenyl)-7-methoxy-2-(3-methoxy-4-
benzyloxyphenyl) benzofuran (22b)
Yield 50%, m.p. 155-156 °C. [Found: C, 72.83; H, 5.38. C27H24O6 requires C, 72.96; H,
5.44%]; Rf (10% EtOAc/hexane) 0.28; 1HNMR (400 MHz, CDCl3) δ 7.77(d, J=15.9Hz, 1H,
CH=CHCO), 7.46(d, J= 8.0Hz, 1H), 7.32-7.42(m, 7H), 6.98(s, 1H), 6.95(d, J=8.0Hz, 1H),
6.89(s, 1H), 6.42(d, J=15.9Hz, 1H, CH=CHCO), 5.22(s, 2H, OCH2Ph), 4.07(s, 3H, OCH3),
13
4.00(s, 3H, OCH3), 3.83(s, 3H, OCH3); C NMR (100 MHz, CDCl3) δ 165.1, 154, 152.9,
146.5, 145.1, 144, 142.8, 121.3, 120.7, 116.5, 112.9, 112.4, 112.2, 113, 109.3, 109, 106.8,
104.1, 75.4, 59, 55.4, 56.1, 52.4; IR(cm-1, KBr): 1702, 1581, 1510, 1455, 1158.
4.11 Preparation of Egonol (I)
Lithium aluminium hydride (0.025 g, 0.65 mmol) was added to a solution of compound
17a (0.025 g, 0.068 mmol) in THF (4.0 mL) at room temperature. Reaction mixture was
14

ACCEPTED MANUSCRIPT
refluxed for 10 h and then cooled to room temperature. It was then decomposed slowly with
ice-cooled water followed by 5% H2SO4 and extracted with ether (3×15 mL). The combined
organic layer was washed with water and dried over sodium sulfate. The solvent was
removed under reduced pressure and the residue obtained was chromatographed over silica
gel using hexane: ethyl acetate (8:2) as an eluent to afford Egonol (I, 0.015 g, 69%), m.p.
112-113 °C, as a white solid. [Found: C, 68.70; H, 5.38. C21H20O6 requires C, 68.47; H,
1
5.47%]; Rf (20% EtOAc/hexane) 0.23; HNMR (400 MHz, CDCl3) δ 7.40(d, J=8.4Hz, 1H),
7.33(bs, 1H), 6.98(bs, 1H), 6.88(d, J=8.4Hz, 1H), 6.80(s, 1H), 6.44(bs, 1H), 6.01(s, 2H,
OCH2O), 4.03(s, 3H, OCH3), 3.71(t, J=7.5Hz, 2H, γ-CH2), 2.78(t, J=7.5Hz, 2H, α-CH2),
13
1.92-1.97(m, 2H, β-CH2); C NMR (100 MHz, CDCl3) δ 156.7, 148.4, 148.2, 145, 142.6,
137.5, 131.2, 125.9, 119.7, 115.0, 108.8, 107.4, 105.3, 101.2, 101, 69.2, 62.3, 59.7, 54.1,
53.1, 37.6, 36; IR(cm-1, KBr): 3357, 1520, 1445, 1151
4.12 Preparation of Homoegonol (II)
Lithium aluminium hydride (0.15 g, 3.9 mmol) was added to a solution of compound 18a
(0.16 g, 0.418 mmol) in THF (15 mL) at room temperature. Reaction mixture was refluxed
for 10 h and then cooled to room temperature. It was then decomposed slowly with ice-
cooled water followed by 5% H2SO4 and extracted with ether (3×20 mL). The combined
organic layer was washed with water and dried over sodium sulfate. The solvent was
removed under reduced pressure and the residue obtained was chromatographed over silica
gel using hexane: ethyl acetate (8:2) as an eluent to afford Homoegonol (II, 0.1 g, 70%),
m.p. 123-125 °C, as a white solid. [Found: C, 70.03; H, 6.37. C20H22O5 requires C, 70.15; H,
1
6.47%]; Rf (20% EtOAc/hexane) 0.28; HNMR (400 MHz, CDCl3) δ 7.46(dd, J=1.8Hz,
8.7Hz, 1H), 7.37(d, J=1.8Hz, 1H), 6.99(bs, 1H), 6.93(d, J=8.7Hz, 1H), 6.84(s, 1H), 6.64(bs,
1H), 4.05(s, 3H, OCH3), 4.04(s, 3H, OCH3), 3.93(s, 3H, OCH3), 3.72(t, J=7.5Hz, 2H, γ-
13
CH2), 2.79(t, J=7.5Hz, 2H, α-CH2), 1.93-1.98(m, 2H, β-CH2), 1.74(bs, 1H, OH); C NMR
(100 MHz, CDCl3) δ 158.7, 147.4, 146.3, 144.2, 141.5, 133.2, 119.7, 119.5, 112.5, 111.8,
111.1, 109.8, 108.9, 62.3, 56.7, 55.5, 32.5, 34.1, 33.4, 30.6; IR(cm-1, KBr): 3374, 1515,
1450, 1161.
4.13 Preparation
benzofuran (23)
of
5-(3-hydroxypropyl)-7-methoxy-2-(3,4,5-trimethoxyphenyl)
Lithium aluminium hydride (0.106 g, 2.8 mmol) was added to a solution of compound
16a (0.412 g, 1 mmol) in THF (5 mL) at 0 °C and the reaction mixture was stirred at room
temperature for 4-5 h. Reaction mixture was then cooled to room temperature. It was then
decomposed slowly with ice-cooled water followed by 5% H2SO4 and extracted with ether
(2×10 mL). The combined organic layer was washed with water and dried over sodium
sulfate. The solvent was removed under reduced pressure and the residue obtained was
chromatographed over silica gel using hexane: ethyl acetate (9:1) as an eluent to afford
compound (23, 0.25 g, 67%), as a thick liquid. [Found: C, 67.80; H, 6.50. C21H24O6 requires
1
C, 67.72; H, 6.49%]; Rf (10% EtOAc/hexane) 0.25; HNMR (400 MHz, CDCl3) δ 7.08(s,
2H), 6.99(bs, 1H), 6.89(s, 1H), 6.66(d, J=1.2Hz, 1H), 4.04(s, 3H, OCH3), 3.96(s, 6H, 2-
OCH3), 3.89(s, 3H, OCH3), 3.72(t, J=7.2Hz, 2H, γ-CH2), 2.79(t, J=7.2Hz, 2H, α-CH2),
1.95(m, 2H, β-CH2), 1.64(bs, 1H, OH); 13C NMR (100 MHz, CDCl3) δ 13C NMR (100 MHz,
15

ACCEPTED MANUSCRIPT
CDCl3) δ 160.2, 147.3, 145.2, 144.8, 142.8, 135.6, 119, 112.8, 111.7, 109.8, 107.9, 65.3,
57.5, 56, 52.9, 32.8, 33.7, 33, 31.4; IR(cm-1, KBr): 3361, 1512, 1446, 1160.
4.14 Preparation of 5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-(3,4,5-trimethoxyphenyl)
benzofuran (24)
A solution of 16a (0.04 g, 0.1 mmol) in THF (6mL) containing 5% Pd/C (100 mg) was
stirred under H2 pressure (44 psi) at room temperature for 10-12 h. The reaction mixture
was filtered through a short column of silica gel to remove the catalyst. The solvent from the
filtrate was removed under reduced pressure. The residue obtained was purified by
chromatography on a silica gel using hexane: ethyl acetate (8:2) as an eluent to give
compound 24 (0.034 g, 85%), m.p. 58-59 °C as a solid. [Found: C, 66.50; H, 6.40. C23H26O7
1
requires C, 66.65; H, 6.32%]; Rf (20% EtOAc/hexane) 0.47; HNMR (400 MHz, CDCl3) δ
7.07(s, 2H), 6.9(d, J=1.5Hz, 1H), 6.88(s, 1H), 6.65(d, J=1.5Hz, 1H), 4.14(q, J=7.5Hz, 2H,
OCH2CH3), 4.03(s, 3H, OCH3), 3.95(s, 6H, 2× OCH3), 3.88(s, 3H, OCH3), 3.02(t, J= 7.8Hz,
13
2H, CH2CH2CO), 2.67(t, J=7.8Hz, 2H, CH2CH2CO), 1.24(t, J=7.5Hz, 3H, OCH2CH3); C
NMR (100 MHz, CDCl3) δ 168.9, 150.7, 148.4, 146.0, 144.6, 142.3, 140, 133.2, 121.5,
118.7, 117, 116.5, 112.4, 111, 109.8, 105.6, 61.5, 56.7, 56.1, 54.2, 36.4, 29.8, 14.7; IR(cm-1,
KBr): 1728, 1515, 1440, 1156.
4.15 General procedure for preparation of 5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-
aryl benzofurans (25-31)
A solution of α, β unsaturated esters (0.1 mmol) in THF (6 mL) containing 5% Pd/C (100
mg) was stirred under H2 pressure (44 psi) at room temperature for 10-12h. The reaction
mixture was filtered through a short column of silica gel to remove the catalyst. The solvent
from the filtrate was removed under reduced pressure. The residue obtained was purified by
chromatography on a silica gel using hexane: ethyl acetate (9:1) as an eluent to give
corresponding dihydroesters except compound 28.
4.15.1 5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-(3,4
methylenedioxyphenyl)benzofuran(25)
Thick liquid, Yield 82%; [Found: C, 68.70; H, 5.38. C21H20O6 requires C, 68.47; H, 5.47%];
1
Rf (10% EtOAc/hexane) 0.45; HNMR (400 MHz, CDCl3) δ 7.39(bd, J=7.8Hz, 1H),
7.32(bs, 1H), 6.97(bs, 1H), 6.87(d, J=7.8Hz, 1H), 6.79(s, 1H), 6.36(bs, 1H), 6.0(s, 2H,
OCH2O), 4.02(s, 3H, OCH3), 3.01(t, J= 7.5 Hz, 2H, COCH2CH2-Ar), 2.66(t, J=7.5 Hz, 2H,
COCH2CH2-Ar), 4.14(q, J=7.2Hz, 2H, OCH2CH3), 1.25(t, J=7.2Hz, 3H, OCH2CH3); 13C
NMR (100 MHz, CDCl3) δ 168, 150.2, 148, 147.4, 146.5, 142.6, 142.3, 140, 133.2, 120.7,
119.2, 116.8, 116, 113.4, 111.6, 109.9, 105, 98.5, 62.5, 57.7, 34.8, 30.2, 15.4; IR(KBr):
1726, 1510, 1441, 1150.
4.15.2 5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-(3,4-dimethoxyphenyl)benzofuran(26)
White solid, Yield 71%, m.p. 110-112 °C; [Found: C, 68.78; H, 6.21. C22H24O6 requires C,
1
68.73; H, 6.29%]; Rf (10% EtOAc/hexane) 0.42; HNMR (400 MHz, CDCl3) δ 7.45(dd,
16

ACCEPTED MANUSCRIPT
J=1.8Hz, 8.7Hz, 1H), 7.36(d, J=1.8Hz, 1H), 6.98(d, J=1.2Hz, 1H), 6.92(d, J=8.7Hz, 1H),
6.83(s, 1H), 6.64(d, J=1.2Hz, 1H), 4.14(q, J=6.9Hz, 2H, OCH2CH3), 4.03(s, 3H, OCH3),
3.94(s, 3H, OCH3), 3.93(s, 3H, OCH3), 3.02(t, J=7.5Hz, 2H, CH2CH2CO), 2.67(t, J=7.5Hz,
13
2H, CH2CH2CO), 1.25(t, J=6.9Hz, 3H, OCH2CH3); C NMR (100 MHz, CDCl3) δ 167.5,
150.1, 148, 146.6, 145.2, 142.6, 139.2, 134, 122.6, 118.3, 117.6, 115.8, 113.2, 110.9, 109.3,
106.5, 62.5, 56.5, 56.1, 33, 32.7, 14.9; IR(KBr): 1729, 1505, 1447, 1158
4.15.3
5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-(3-methoxy-4-
benzyloxyphenyl)benzofuran(27)
White solid, Yield 75%, m.p. 111-112 °C; [Found: C, 66.50; H, 6.40. C23H26O7 requires C,
1
66.65; H, 6.32%]; Rf (10% EtOAc/hexane) 0.40; HNMR (400 MHz, CDCl3) δ 7.45(d,
J=8.1Hz, 1H), 7.3-7.4(m, 6H), 6.97(bs, 1H), 6.93(d, J=8.1Hz, 1H), 6.82(s, 1H), 6.63(bs,
1H), 5.20(s, 2H, OCH2Ph), 4.14(q, J=7.2Hz, 2H, OCH2CH3), 4.02(s, 3H, OCH3), 3.99(s, 3H,
OCH3), 3.01(t, J=7.5Hz, 2H, CH2CH2CO), 2.66(t, J=7.5Hz, 2H, CH2CH2CO), 1.25(t,
J=7.2Hz, 3H, OCH2CH3); 13C NMR (100 MHz, CDCl3) δ 172.4, 158.5, 149.4, 148.3, 137.5,
136.9, 132.2, 128.4, 125.9, 123.9, 123.1, 119.7, 116.1, 115.0, 100.9, 100.2, 72.5, 60.3, 58.7,
58.1, 57.3, 39.6, 38.5, 32.2, 16.2; IR(cm-1, KBr): 1726, 1500, 1445, 1150.
4.15.4 Preparation
of
5-(2-ethoxycarbonly)ethyl)-7-methoxy-2-(3-methoxy-4-
hydroxyphenyl) benzofuran (28)
A solution of 19a (0.1 g, 0.22 mmol) in THF (4 mL) containing 5% Pd/C (25 mg) was
stirred under H2 pressure (60 psi) at room temperature for 12 h. The reaction mixture was
filtered through a short column of silica gel to remove the catalyst. The solvent from the
filtrate was removed under reduced pressure. The residue obtained was purified by
chromatography on a silica gel using hexane: ethyl acetate (7:3) as an eluent to give
compound 28 (0.065 g, 80%) as a thick liquid. [Found: C, 68.10; H, 6.10. C21H22O6 requires
1
C, 68.09; H, 5.98%]; Rf (30% EtOAc/hexane) 0.32; HNMR (400 MHz, CDCl3) δ 7.38(dd,
J=1.8 Hz, 8.1Hz, 1H), 7.36(bs, 1H), 6.98(bs, 1H), 6.96(d, J=8.1Hz, 1H), 6.80(s, 1H),
6.63(bs, 1H), 5.84(s, 1H, OH), 4.14(q, J=7.2Hz, 2H, OCH2CH3), 4.02(s, 3H, OCH3), 3.99(s,
3H, OCH3), 3.01(t, J=7.5Hz, 2H, CH2CH2CO), 2.66(t, J=7.5Hz, 2H, CH2CH2CO), 1.24(t,
13
J=7.2Hz, 3H, OCH2CH3); C NMR (100 MHz, CDCl3) δ 164.2, 152.1, 147.5, 146, 145.8,
143.4, 139.3, 133.9, 122.5, 117.4, 117.1, 116.2, 113.7, 109.9, 109.1, 105.8, 64, 56.6, 55.4,
35.5, 30.5, 16.2; IR(cm-1, KBr): 3424, 1725, 1510, 1444, 1156.
4.15.5 5-(2-methoxycarbonly)ethyl)-7-methoxy-2-(3,4-dimethoxyphenyl)
(29)
benzofuran
Yield 60%, m.p. 120-122 °C; [Found: C, 67.64; H, 5.72. C21H22O6 requires C, 68.09; H,
1
5.98%]; Rf (30% EtOAc/hexane) 0.43; HNMR (400 MHz, CDCl3) δ 7.40(dd, J=1.8Hz,
8.1Hz, 1H), 7.38(d, J=1.8z, 1H), 7.00(bs, 1H), 6.95(d, J=8.1Hz, 1H), 6.86(s, 1H), 6.66(bs,
1H), 4.06(s, 3H, OCH3), 4.01(s, 3H, OCH3), 3.95(s, 3H, OCH3), 3.71(s, 3H, OCH3), 3.05(t,
J=7.5Hz, 2H, CH2CH2CO), 2.71(t, J=7.5Hz, 2H, CH2CH2CO); 13C NMR (100 MHz,
CDCl3) δ 169.5, 150.6, 149.2, 146.6, 145.8, 143.5, 138.6, 134.5, 123.7, 118, 117.9, 116.3,
17

ACCEPTED MANUSCRIPT
112.2, 110.3, 109.1, 108.5, 57.2, 56.5, 54.3, 51.1, 35.4, 29.8; IR(cm-1, KBr): 1729, 1515,
1440, 1155.
4.15.6 5-(2-methoxycarbonly)ethyl)-7-methoxy-2-(3-methoxy-4-benzyloxyphenyl)
benzofuran (30)
Yield 75%, m.p. 121-123 °C; [Found: C, 72.31; H, 5.45. C27H26O6 requires C, 72.63; H,
5.86%]; Rf (30% EtOAc/hexane) 0.39; 1HNMR (400 MHz, CDCl3) δ 7.30-7.48(m, 7H),
6.98(d, J=1.8Hz, 1H), 6.93(d, J=8.7Hz, 1H), 6.82(s, 1H), 6.62(d, J=1.8Hz, 1H), 5.20(s, 2H),
13
4.03(s, 3H), 3.98(s, 3H), 3.68(s, 3H), 3.01(t, J=7.8Hz, 2H), 2.68(t, J=7.8Hz, 2H); C NMR
(100 MHz, CDCl3) δ 165.4, 155.5, 147.4, 146, 137.8, 136.5, 131.7, 128.2, 126.8, 123.3, 123,
118.2, 116.5, 115.6, 115.0, 109.7, 109.2, 100.5, 72.6, 51.7, 58, 55.8, 35.2, 31.4; IR(cm-1,
KBr): 1726, 1515, 1448, 1149.
4.15.7
5-(2-methoxycarbonly)ethyl)-7-methoxy-2-(3-methoxy-4-hydroxyphenyl)
benzofuran (31)
White solid, Yield 77%, m.p. 71-73 °C; [Found: C, 67.15; H, 5.48. C20H20O6 requires C,
1
67.40; H, 5.66%]; Rf (30% EtOAc/hexane) 0.33; HNMR (400 MHz, CDCl3) δ 7.38(dd,
J=1.8Hz, J=8.4Hz, 1H), 7.36(d, J=1.8Hz, 1H), 6.98(d, J=1.5Hz, 1H), 6.97*d, J=8.4Hz, 1H),
6.80(s, 1H), 6.62(d, J=1.5Hz, 1H), 5.82(s, 1H, OH), 4.03(s, 3H, OCH3), 3.99(s, 3H, OCH3),
3.68(s, 3H, OCH3), 3.02(t, J=7.5Hz, 2H, CH2CH2CO), 2.68(t, J=7.5Hz, 2H, CH2CH2CO);
13C NMR (100 MHz, CDCl3) δ 162.6, 155, 148.4, 146.6, 138.9, 135.4, 131.2, 127.9, 127.8,
124.3, 123.5, 119.2, 116.4, 115.6, 109.2, 100.8, 52.7, 57.3, 55, 35, 32.3; IR(cm-1, KBr):
1715, 1510, 1445, 1140.
4.15.7 5-(2-methoxycarbonly)ethyl)-7-methoxy-2-(3,4-methylenedioxyphenyl)
benzofuran (32)
White solid, Yield 80%, m.p. 114-115 °C; [Found: C, 67.65; H, 5.25. C20H18O6 requires C,
1
67.80; H, 5.10%]; Rf (30% EtOAc/hexane) 0.46; HNMR (400 MHz, CDCl3) δ 7.36(d,
J=1.8Hz, 1H), 6.97(bs, 1H), 7.39(dd, J=8.4Hz, 1.8Hz, 1H), 6.87(d, J=8.4Hz, 1H), 6.79(s,
1H), 6.62(d, J=1.2Hz, 1H), 6.01(s, 2H, OCH2O), 4.02(s, 3H, OCH3), 3.86(s, 3H, OCH3),
3.01(t, J=7.5Hz, 2H, OCH2CH2Ar), 2.68(t, J=7.5Hz, 2H, OCH2CH2Ar); 13C NMR (100
MHz, CDCl3) δ 168.4, 151.3, 148.2, 147.3, 145.5, 142.3, 142, 139.8, 133.5, 121.6, 119.8,
115.7, 114.5, 112.3, 111.5, 109.1, 104.2, 97.6, 62.5, 51.7, 35.8, 31.4; IR(cm-1, KBr): 1734,
1513, 1456, 1148.
4.16 Preparation of Egonoic acid (III)
Sodium hydroxide (1N, 0.2 mL, 0.2 mmol) was added to a solution of compound 25
(0.05 g, 0.13 mmol) in methanol (3 mL) and refluxed for 30 min. Methanol was removed
under reduced pressure and water(4 mL) was added and cooled to 10 °C. It was then
acidified with HCl (1N, 2mL) and the precipitate obtained was extracted with ether (1×20
mL). The combined organic layer was washed with water (2×20 mL), dried over sodium
sulfate and evaporated to give a solid. This crude mass was chromatographed on silica gel
using hexane: ethyl acetate (1:1) as an eluent and afforded Egonoic acid (0.027 g, 58%),
18

ACCEPTED MANUSCRIPT
m.p. 180-182 °C, as a white crystalline solid. [Found: C, 67.34; H, 4.50. C19H16O6 requires
C, 67.05; H, 4.74 %]; Rf (50% EtOAc/hexane) 0.61; 1HNMR (400 MHz, CDCl3, DMSO-d6)
δ 7.40(dd, J=8.1Hz, 1.8Hz, 1H), 7.32(d, J=1.8Hz, 1H), 6.97(bs, 1H), 6.87(d, J=8.1Hz, 1H),
6.79(s, 1H), 6.64(bs, 1H), 6.01(s, 2H, OCH2O), 4.03(s, 3H, OCH3), 3.03(t, J=7.5Hz, 2H,
CH2CH2CO), 2.73(t, J=7.5Hz, 2H, CH2CH2CO); 13C NMR (100 MHz, CDCl3) δ 162.5,
152.4, 147.9, 146.3, 145.8, 142, 141.3, 138.8, 134.5, 122.5, 119.2, 116.7, 114.5, 112.7,
110.5, 109, 104.8, 96.9, 56.7, 34.8, 32.5; IR(cm-1, KBr): 3424, 1725, 1510, 1444, 1156.
4.17 General procedure for preparation of 5-(2-carboxyethyl)-7-methoxy-2-
arylbenzofurans (33-35)
Sodium hydroxide (1N, 0.25 mL, 0.25 mmol) was added to a solution of dihydroesters
(24, 26 & 28, 0.2 mmol) in methanol (5 mL) and refluxed for 30 min. Methanol was
removed under reduced pressure and water (5 mL) was added and cooled to 10 °C. It was
then acidified with HCl (1N, 2.5 mL) and the precipitate obtained was extracted with ether
(2×20 mL). The combined organic layer was washed with water (2×20 mL), dried over
sodium sulfate and evaporated to give a solid. Solid mass was chromatographed on silica gel
using hexane: ethyl acetate (8.5:1.5) as an eluent to afford corresponding acids in 75-90%
yield.
4.17.1 5-(2-carboxyethyl)-7-methoxy-2-(3,4,5-trimethoxybenzyl)benzofuran(33)
Yield 86%, m.p. 121-122 °C; [Found: C, 65.50; H, 5.80. C21H22O7 requires C, 65.27; H,
1
5.74 %]; Rf (15% EtOAc/hexane) 0.65; HNMR (400 MHz, CDCl3, DMSO-d6) δ 7.14(s,
2H), 7.07(bs, 1H), 6.96(s, 1H), 6.72(bs, 1H), 4.09(s, 3H, OCH3), 4.02(s, 6H, 2×OCH3),
3.95(s, 3H, OCH3), 3.10(t, J=7.5Hz, 2H, CH2CH2CO), 2.81(t, J=7.5Hz, 2H, CH2CH2CO);
13C NMR (100 MHz, CDCl3) δ 162, 152.8, 148.5, 147.2, 145.6, 142.5, 142.1, 139.6, 134.7,
123.2, 118.9, 116.5, 114, 112.3, 110.1, 108.6, 104.1, 57.2, 56.8, 56.7, 55.4, 34.5, 32.8;
IR(cm-1, KBr): 3435, 1714, 1510, 1438, 1150.
4.17.2 5-(2-carboxyethyl)-7-methoxy-2-(3,4-dimethoxybenzyl)benzofuran(34)
Yield 75%, m.p. 156-157 °C; [Found: C, 67.80; H, 5.50. C20H20O6 requires C, 67.40; H,
1
5.65 %]; Rf (15% EtOAc/hexane) 0.57; HNMR (400 MHz, CDCl3, DMSO-d6) δ 7.45(dd,
J=1.8Hz, J=8.4Hz, 1H), 7.36(d, J=1.8Hz, 1H), 6.99(d, J=1.2Hz, 1H), 6.92(d, J-8.4Hz, 1H),
6.84(s, 1H), 6.64(d, J=1.2Hz, 1H), 4.03(s, 3H, OCH3), 3.98(s, 3H, OCH3), 3.92(s, 3H,
OCH3), 3.03(t, J=7.2Hz, 2H, CH2CH2CO), 2.47(t, J=7.2Hz, 2H, CH2CH2CO); 13C NMR
(100 MHz, CDCl3) δ 162, 153.2, 148.6, 147, 145.3, 141.9, 141.7, 139, 135.3, 122.9, 118.2,
115.9, 114.5, 113.6, 110.5, 108.7, 103.9, 56.7, 55.8, 54.6, 35.5, 31.7; IR(cm-1, KBr): 3523,
1704, 1510, 1439, 1144.
4.17.3 5-(2-carboxyethyl)-7-methoxy-2-(3-methoxy-4-hydroxybenzyl)benzofuran(35)
Yield 90%, m.p. 158-159 °C; [Found: C, 66.70; H, 5.30. C19H18O6 requires C, 66.66; H,
1
5.23 %]; Rf (15% EtOAc/hexane) 0.42; HNMR (400 MHz, CDCl3, DMSO-d6) δ 7.39(dd,
J=1.8Hz, J=8.1Hz, 1H), 7.37(d, J=1.8Hz, 1H), 6.99(s, 1H), 6.98(d, J-8.1Hz, 1H), 6.81(s,
1H), 6.64(bs, 1H), 5.88(s, 1H, OH), 4.03(s, 3H, OCH3), 3.99(s, 3H, OCH3), 3.04(t, J=7.2Hz,
19

ACCEPTED MANUSCRIPT
13
2H, CH2CH2CO), 2.74(t, J=7.2Hz, 2H, CH2CH2CO); C NMR (100 MHz, CDCl3) δ 165,
155.6, 150.6, 149.3, 145, 144.7, 142.5, 138.7, 135.2, 123.8, 117.9, 115, 114.8, 113.7, 111.5,
109.7, 104.2, 58.2, 55.9, 34.5, 30.6; IR(cm-1, KBr): 3523, 1704, 1510, 1439, 1144.
Acknowledgements
The authors wish to thank, the management of Garware Research Center, Department of
Chemistry from Pune University for providing all the facilities required for studies.
Supplementary data
1H NMR, 13C NMR
References and Notes:
1. Tsai, I.L.; Hsieh, C. F.; Duh, C. Y. Phytochemistry, 1998, 48, 1371-1375.
2. Honson, S. W.; Crowford, M.; Thanasingh, D. P. J. Phytochemistry, 1981, 20, 1162-
1164.
3. Ward, R. S. Nat. Prod. Rep. 1999, 16, 75-96.
4. Forbes, M.; Zilliken, F.; Roberts, C.; Gyorgy, P. J. Am. Chem. Soc., 1958, 80, 385-389.
5. Okada, H. J. Pharm. Soc. Jpn. 1915, 657.
6. Segal, R.; Milo-Goldzweig, I.; Sokoloff, S.; Zaitschek, D.V. J. Chem. Soc. (C), 1967,
2402-2404.
7. De Diaz, A. M. P. Phytochemistry, 1997, 44, 345-346.
8. Talapatra, B.; Ray, T.; Talapatra, S. K. Indian J. Chem. 1976, 14B, 613.
9. Hirano, T.; Goto, M.; Oka, K. Life Sci. 1994, 55, 1061-1069.
10. Shin, I. S.; Ahn, K. S.; Shin, N. R.; Jeon, C. M.; Kwon, O. K.; Chin, Y. W.; Lee, K.; Oh,
S. R. Arch Pharm. Res. 2014, 37, 1201-10.
11. Pollyanna, F.O.; Jaqueline, L. D.; Camila, S. B.; Alba, R. B. A.; Patrícia, M. P.; Denise,
C. T. Cytotechnology, 2015, 67, 1-6.
12. Yang, Z.; Hon, P. M.; Chui, K. Y.; Xu, Z. L.; Chang, H. M. Tetrahedron Lett. 1991, 32,
2061-2064.
13. a) Seemuth, P.D.; Zimmer, H. J. Org. Chem. 1978, 43, 3063-3065. (b) Watanabe, M.;
Kawanishi, K.; Furukawa, S. Chem. Pharm. Bull. 1991, 39, 579-583. (c) Guy, A.; Guette,
J. P. Synthesis, 1980, 222-223. (d) Duffley, R. P.; Stevenson, R. J. Chem. Soc. Perkin
Trans. I, 1977, 802-804. (e) Villemin, D.; Goussu, D. Heterocycles, 1989, 29, 1255-1261.
14. (a) Kumar, A.; Gangwar, M.; Prakasham, A. P.; Mhatre, D.; Kalita, A. C.; Ghosh, P.
Inorg. Chem. 2016, 55, 2882–2893. (b) Naveen, M.; Reddy, Ch. U.; Hussain, M.;
Chaitanya, M.; Narayanaswamy, G. J. Heterocyclic Chem. 2013, 50, 1064-66. (c)
Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1969, 22, 1329-30. (d) Mali, R. S.; Massey, A.
P. J. Chem. Res. 1998, 5, 1109-1120. (e) Choi, D. H.; Hwang, J. W.; Lee, H. S.; Yang, D.
M.; Jun, J.-G. Bull. Korean Chem. Soc. 2008, 29, 1594-1596.
15. (a) Iyer, S.; Ramesh, C. Tetrahedron Lett. 1999, 40, 4719-4720. (b) Villemin, D.;
Nechab,B. J. Chem. Res. (S), 2000, 9, 429-431. (c) Larhed, M.; Hallberg, A. J. Org.
Chem. 1996, 61, 9582-9584. (d) Jeffery, T. Tetrahedron lett. 1994, 35, 3051-3054.
20

ACCEPTED MANUSCRIPT
16. Henry, T. A.; Sharp, T.M. J. Chem. Soc. 1930, 2088.
17. Hopkins, C. Y.; Ewing, D. F.; Chisholm, M. J. Can. J. Chem. 1967, 45, 1425-1429.
18. Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C. J. Org. Chem. 1992, 57,
7248-7257.
19. Hutchinson, S. A.; Luetjens, H.; Scammells, P. J. Bioorg. Med. Chem. Lett. 1997, 7,
3081-3084.
20. Deya, P. M.; Dopico, M.; Morey, A. C. R. J.; Saa, J. M. Tetrahedron, 1987, 43, 3523-
3532.
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