A new synthetic route of 2-aroyl- and 2-benzyl-benzofurans and their application in the total synthesis of a metabolite isolated from dorstenia gigas

Article abstract of DOI:10.1071/CH08243

The Lewis acid-catalyzed cyclization of the (Z)-3-(dimethylamino)-2- aryloxy-1-arylprop-2-en-1-ones 4ah leads to a regioselective and short synthesis of 2-aroylbenzofurans 2ah. The WolffKishner reduction of the latter yielded a series of substituted 2-ben

Full text of DOI:10.1071/CH08243

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 991–999
A New Synthetic Route of 2-Aroyl- and 2-Benzyl-Benzofurans
and their Application in the Total Synthesis of a Metabolite
Isolated from Dorstenia gigas
Christian Correa,A María del Carmen Cruz,B,C Fabiola Jiménez,A
L. Gerardo Zepeda,A and Joaquín TamarizA,C
ADepartamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas, Instituto
Politécnico Nacional Prol. Carpio y Plan de Ayala, 11340 México, DF, Mexico.
BCentro de Investigación en Biotecnología Aplicada, Instituto Politécnico Nacional,
Carretera Estatal Sta Inés Km 1.5, Tepetitla, 90700 Tlaxcala, Mexico.
CCorresponding authors. Email: jtamariz@woodward.encb.ipn.mx; carmencruz25@yahoo.com.mx
The Lewis acid-catalyzed cyclization of the (Z)-3-(dimethylamino)-2-aryloxy-1-arylprop-2-en-1-ones 4a–h leads to a
regioselective and short synthesis of 2-aroylbenzofurans 2a–h. The Wolff–Kishner reduction of the latter yielded a series
of substituted 2-benzylbenzofurans 3a–h. This methodology was applied in the first total synthesis of the metabolite
2-(4-hydroxybenzyl)-6-methoxybenzofuran 1, which was isolated from the tropical plant Dorstenia gigas, and obtained
through a six-step route and in a 24% overall yield.
Manuscript received: 8 June 2008.
Final version: 25 October 2008.
OH
Introduction
The genus Dorstenia (Moraceae) has attracted special interest
due to the isolation of a large variety of heterocyclic com-
pounds such as furocoumarins, benzofurans, and flavonoids.[1–7]
The presence of these metabolites has been associated with
the biological properties exhibited by some species of this
genus, when used in folk medicine, mainly for the treat-
ment of skin diseases.[8–12] Among the metabolites isolated
from Dorstenia gigas, a succulent shrub growing on Soco-
tra Island whose extracts have shown anti-inflammatory and
antibiotic activities,[13] one can find 2-(4-hydroxybenzyl)-
6-methoxybenzofuran 1 (Scheme 1),[13] which is a natural
product exhibiting antifungal activity in the Cladosporium bio-
assay, and which displays an uncommon 2-benzylbenzofuran
framework.[14] Owing to the medicinal and horticultural interest
of D. gigas, a micropropagation technique has been developed
with the intention of reproducing this threatened species.[15]
However, 2-aroylbenzofurans and 2-benzylbenzofurans have
been synthesized, and some of them have exhibited significant
biological properties, such as estrogenic, spasmolytic, antiviral,
antimicrobial, andanticanceractivities.[16–20] Inanintenseeffort
to synthesize 2-substituted benzofurans,[21–24] many methodolo-
gies that lead to the preparation of 2-aroylbenzofurans have been
reported,[16–20,23,25–29] whereas only a few approaches have been
found for the synthesis of 2-benzylbenzofurans.[16,26,30–33]
Recently, we reported a new straightforward synthesis
of 2-carbomethoxy- and 2-acetyl-benzofurans, through an
intramolecular cyclization of enaminones promoted by Lewis
acids.[34] This strategy allowed us to prepare a series of natu-
ral benzofurans in good overall yields.[35] Therefore, the ready
access to the construction of the benzofuran scaffold by this
O
MeO
1
Scheme 1.
N
O
RЈ
R
RЈ
R
O
X
O
4
2 X ϭ O
3 X ϭ H, H
Scheme 2.
methodology prompted us to extend it to the preparation of the
substituted 2-aroyl- and 2-benzyl-benzofurans 2 and 3, respec-
tively, by using enaminones 4 as their precursors (Scheme 2), as
well as to the development of the first total synthesis of natural
compound 1.
Results and Discussion
Phenoxyacetophenones 8a–h were prepared in high yields (80–
88%) by treating the corresponding 2-bromoacetophenones
6a–e with phenols 7a,b in the presence of potassium carbonate
in acetone at reflux for 12 h (Scheme 3). 2-Bromoacetophenones
© CSIRO 2008
10.1071/CH08243
0004-9425/08/120991

992
C. Correa et al.
RЈ
RЈ
Br2, CH2Cl2
K2 CO3
ϩ
R
R
R
or
Acetone, reflux
12 h
OH
1؅
3؅
1
MeO
O
Br
MeO
2؅
2
NBS, MeCN
O
O
O
80–88%
8a–h
7a RЈ ϭ H
7b RЈ ϭ OMe
6a–e
5a R ϭ H
5b R ϭ 3-Me
5c R ϭ 4-Me
5d R ϭ 4-F
DMFDMA
90°C, 24 h
∼80%
5e R ϭ 3-OMe
RЈ
RЈ
4
RЈ
NH2NH2
(CH2OH)2
Y
3
R
R
ZnCl2, CH2Cl2
R
2
KOH
150°C, 4 h
∼86%
20°C, 72 h
∼70%
3؅
1؅
O
1
MeO
O
O
6
O
2؅
2
MeO
MeO
O
3a–h
2a–h
Scheme 3.
4a–h Y ϭ NMe2
Table 2. Preparation of 2-aroylbenzofurans 2a–hA and 2-benzylbenzo-
furans 3a–hB
Table 1. Preparation of methyl 2-aryloxy-3-dimethylaminopropeno-
ates 4a–h
Under a N2 atmosphere, with 3.0 mol equiv. of DMFDMA at 90◦C for 24 h
Entry
(R)
(Rꢀ)
2 [%]C
3 [%]C
Entry
8 (R)
(Rꢀ)
4 [%]A
1
2
3
4
5
6
7
8
(H)
H
H
H
H
2a (72)
2b (70)
2c (63)
2d (76)
2e (55)
2f (78)
2g (65)
2h (79)
3a (89)
3b (90)
3c (91)
3d (78)
3e (90)
3f (88)
3g (90)
3h (75)
1
2
3
4
5
6
7
8
8a (H)
H
H
H
H
4a (88)
4b (86)
4c (84)
4d (91)
4e (80)
4f (89)
4g (82)
4h (93)
(3-Me)
(4-Me)
(4-F)
(3-OMe)
(H)
8b (3-Me)
8c (4-Me)
8d (4-F)
8e (3-OMe)
8f (H)
H
H
OMe
OMe
OMe
OMe
OMe
OMe
(4-Me)
(4-F)
8g (4-Me)
8h (4-F)
AUnder a N2 atmosphere, with 5.0 mol equiv. of ZnCl2 in CH2Cl2 as the
solvent at 20◦C for 72 h.
AAfter column chromatography and recrystallization.
BUnder a N2 atmosphere, with 6.5 mol equiv. of NH2NH2, KOH in
(CH2OH)2 as the solvent at 150◦C for 4 h.
6a–e are commercially available or can be prepared by
bromination of the acetophenones 5a–e with bromine in
CHCl3,[36] or in the presence of zinc dust in H2O,[37] or with
N-bromosuccinimide(NBS)inthepresenceofp-toluenesulfonic
acid.[38] Treatment of 8a–h with N,N-dimethylformamide
dimethyl acetal (DMFDMA) at 90◦C for 24 h provided the
respective enaminones 4a–h, also in high yields (Table 1). The
latterwereobtainedasasinglestereoisomer, whosegeometry(Z)
was established by nuclear Overhauser effect experiments: irra-
diation of the signal assigned to protons of the dimethylamino
group of compound 4a produced an enhancement of the sig-
nals corresponding to the aryloxy ring; the same was true for
the irradiation of the vinyl proton with an enhancement of the
acetophenone moiety.
Cyclization of enaminones 4a–h promoted by ZnCl2 as
the Lewis acid furnished the desired 2-aroylbenzofurans 2a–h
(Scheme 3) in fairly good yields (55–79%) (Table 2). Owing
to the low solubility of the catalyst in the solvent, we had
to use a large excess (5.0 mol equiv.) to increase the conver-
sion rate. Other Lewis acids were used such as BF3·OEt2,
AlCl3, and MgBr2 to improve the reaction yields, but they were
less efficient. Also, low yields were obtained when we used
microwave irradiation, in contrast with our previous results.[35]
Reduction of the carbonyl group was carried out under Clem-
mensen conditions (Zn–Hg, HCl)[39,40] to give the correspond-
ing 2-benzylbenzofurans 3a–h (Scheme 3) in low yields. The
CAfter column chromatography or recrystallization.
reduction efficiency was significantly improved when Wolff–
Kishner conditions (NH2NH2, (CH2OH)2, KOH)[26,41] were
used (Table 2).
Once the reaction sequence conditions for the preparation of
2-benzylbenzofurans 3 were established, the synthesis of natu-
ral compound 1 was accomplished under analogous conditions.
The substrate 2-bromoacetophenone 6f[42,43] was prepared from
phenol 5f by protection with benzyl bromide in the presence of
potassium carbonate as the base,[44] followed by a treatment
with bromine in methylene chloride, to give 6f in a 76% over-
all yield (Scheme 4). Substitution of the bromine atom by the
phenoxy group was carried out by treatment of the latter with
7a, to provide 8i in high yield (86%). This product was treated
with DMFDMA at 90◦C for 24 h to give enaminone 4i in good
yield (81%). Treatment of the latter with the Lewis acid led to
2-aroylbenzofuran 2i as a single regioisomer. It is worth noting
that the cyclization of 4i took place within 48 h by using only
3.0 mol equiv. of ZnCl2, in contrast with the longer reaction time
and larger amount of catalyst employed with the general method
(Table 2).
Compound 2i was transformed into the natural product 1
by two alternative pathways. The first consisted of a two-step

Total Synthesis of 2-(4-Hydroxybenzyl)-6-methoxybenzofuran
993
O
O
OBn
Br
(i, ii)
(iii)
MeO
O
HO
BnO
O
6f
8i
5f
(iv)
OBn
OBn
N
O
OBn
(vi)
(v)
MeO
O
O
O
MeO
MeO
O
3i
2i
4i
(vii)
(viii or ix)
OH
4؅
2؅ 3؅
1؅
O
MeO
1
Scheme 4. Reagents and conditions: (i) BnBr, K2CO3, acetone, reflux, 6 h, 95%; (ii) Br2, CH2Cl2, 20◦C, 1 h, 80%; (iii) 7a, K2CO3,
acetone, reflux, 12 h, 86%; (iv) DMFDMA, 90◦C, 24 h, 81%; (v) ZnCl2, CH2Cl2, 20◦C, 48 h, 68%; (vi) Zn–Hg, HCl, EtOH, 65◦C,
8 h, 81%; (vii) H2, Pd/C, EtOAc, 20◦C, 12 h, 77%; (viii) Et3SiH, BF3·Et2O, CH2Cl2, 20◦C, 3 h, 40%; (ix) Zn–Hg, HCl, EtOH, 65◦C,
12 h, 68%.
sequence, starting from a reduction with amalgam of zinc to
give 3i, and followed by a Pd-catalyzed hydrogenation to fur-
nish 1 in a 62% overall yield for the two steps (Scheme 4). The
second pathway was accomplished by reduction of the carbonyl
group and debenzylation of 2i in a single step. To carry out the
latter, we tried two different sets of conditions: (1) treatment
with triethylsilane in the presence of BF3·OEt2 in methylene
chloride at room temperature for 3 h,[45] to give 1 in 40% yield;
(2) application of the same Clemmensen conditions (Zn–Hg,
HCl, 65◦C) used in the first pathway, but increasing the concen-
tration of the reagents and the reaction time (12 h), afforded 68%
of the desired product.[46] Therefore, the latter route was shorter
and more efficient than the former one. The spectral data of the
synthetic compound 1 were identical to those described for the
natural metabolite.[13]
recorded on a Perkin–Elmer (Spectrum 2000) Fourier transform
(FT)-IR spectrometer. 1H (300 MHz) and 13C (75.4 MHz) NMR
spectra were recorded on a Varian Mercury-300 instrument,
with TMS as internal standard. Mass spectra (MS) and high-
resolution mass spectra (HR-MS) were obtained, in electron
impact (EI) (70 eV) and fast-atom bombardment (FAB) modes,
on a Thermo-Finnigan Polaris Q and on a Jeol JMS-AX 505 HA
spectrometer, respectively. Microanalyses were performed by
M-H-WLaboratories(Phoenix,AZ).AnalyticalTLCwascarried
out by using Merck silica gel 60 F254-coated plates, visualized by
long-andshort-wavelengthUVlamps. Flashcolumnchromatog-
raphy was performed on silica gel (230–400 mesh) from Natland
International Co. All air moisture-sensitive reactions were car-
ried out under nitrogen using oven-dried glassware. Methylene
chloride, ethylacetate, andacetonitrilewerefreshlydistilledover
calcium hydride, before use. Acetone was distilled after reflux-
ing over KMnO4 for 4 h. K2CO3 was dried overnight at 200◦C
before being used. All other reagents were used without further
purification.
Conclusions
A new synthetic route for the preparation of the uncommon
2-benzylbenzofurans, 3a–h, is described. It consists of a
sequence of four steps, starting from the reaction between the
series of 2-bromoacetophenones 6a–h and the phenols 7a,b,
and includes an intramolecular cyclization of the corresponding
enaminones 4a–h to give the 2-aroylbenzofurans 2a–h, as the
key step. Reduction of the carbonyl group of the latter yielded
the desired products 3a–h. This methodology was applied to
the first total synthesis of the naturally occurring metabolite 1,
through a six-step sequence, with a 24% overall yield.
General Method of Preparation of 2-Bromoacetophenones
6a–e: 2-Bromoacetophenone 6a
At room temperature and under a N2 atmosphere, NBS (0.66 g,
3.72 mmol) was slowly added to a mixture of 5a (0.50 g,
3.72 mmol) and p-TsOH (0.96 g, 5.58 mmol) in dry acetonitrile
(150 mL). The mixture was heated to 70◦C for 2 h, the solvent
was removed under vacuum, the residue was dissolved with
100 mL of CH2Cl2, and then washed with H2O (3 × 50 mL).
The organic layer was dried (Na2SO4) and the solvent was
removed under vacuum. The residue was purified by column
chromatography over silica gel (40 g, hexane/EtOAc, 98:2), to
give 6a as a white solid (0.63 g, 80%). Retention factor (Rf ) 0.37
(hexane/EtOAc, 85:15). mp 45–46◦C (lit.[47] 46–47◦C).
Experimental
General
Melting points (uncorrected) were determined with an Electro-
thermal capillary melting point apparatus. IR spectra were

994
C. Correa et al.
2-Bromo-4ꢀ-benzyloxyacetophenone 6f
1.93 mmol) in 1 mL of dry acetone afforded 8e as a pale yellow
solid (0.354 g, 81%). Rf 0.33 (hexane/EtOAc, 8:2). mp 76–78◦C
(Found: (M)+ 272.1048. C16H16O4 requires 272.1049). νmax
(KBr)/cm−1 1703, 1597, 1492, 1456, 1433, 1288, 1263, 1198,
1154, 1042, 766, 686. δH (CDCl3) 3.76 (3H, s, OCH3), 3.85 (3H,
s, OCH3), 5.24 (2H, s, OCH2), 6.52–6.56 (3H, m, H2ꢀ, H4ꢀ, H6ꢀ),
7.12–7.18 (2H, m, H5ꢀ, H4), 7.39 (1H, t, J 7.8, H5), 7.51 (1H, dd,
J 2.6, 1.3, H2), 7.55 (1H, ddd, J 7.5, 1.5, 1.2, H6). δC (CDCl3)
55.2, 55.4, 70.7, 101.4, 106.5, 107.2, 112.3, 120.3, 120.4, 129.8,
129.9, 135.7, 159.2, 159.9, 160.8, 194.0. m/z 272 (M+, 13%),
135 (100), 107 (21), 77 (12).
A mixture of 5f (2.0 g, 14.7 mmol) in 20 mL of dry acetone, and
K2CO3 (4.06 g, 29.4 mmol) was heated to reflux for 30 min, and
benzyl bromide (3.77 g, 22.0 mmol) was added dropwise. The
mixture was stirred and heated to reflux for 6 h, filtered, and
the solvent was removed under vacuum. The residue was puri-
fied by column chromatography over silica gel (30 g, hexane/
EtOAc, 85:15), to give 9 as a white solid (3.16 g, 95%).
Rf 0.35 (hexane/EtOAc, 8:2). mp 93–94◦C (lit.[44] 93◦C). At
room temperature and under a N2 atmosphere, bromine (1.42 g,
8.85 mmol) in dry CH2Cl2 (5 mL) was slowly added to a solution
of 9 (2.0 g, 8.85 mmol) in dry CH2Cl2 (5 mL). The mixture was
stirred to 20◦C for 1 h, and washed with a cold saturated solution
of Na2S2O4 (3 × 5 mL). The organic layer was dried (Na2SO4)
and the solvent was removed under vacuum. The residue was
purified by column chromatography over silica gel (40 g, hexane/
EtOAc, 95:5), to give 6f as a white solid (2.16 g, 80%). Rf 0.43
(hexane/EtOAc, 8:2). mp 89–90◦C (lit.[42,43] 88–90◦C).
2-(3,5-Dimethoxyphenoxy)-1-phenylethanone 8f
Following the procedure as for 8a, with 7b (0.20 g, 1.3 mmol) in
2 mL of dry acetone, K2CO3 (0.26 g, 1.88 mmol), and 6f (0.31 g,
1.55 mmol) in 1 mL of dry acetone afforded 8f as a white solid
(0.30 g, 85%). Rf 0.40 (hexane/EtOAc, 8:2). mp 87–88◦C (lit.[47]
87–88◦C).
Preparation of Acetophenones 8a–h:
2-(3-Methoxyphenoxy)-1-phenylethanone 8a
2-(3,5-Dimethoxyphenoxy)-1-(4-tolyl)ethanone 8g
Following the procedure as for 8a, with 7b (0.20 g, 1.3 mmol)
in 2 mL of dry acetone, K2CO3 (0.26 g, 1.88 mmol), and 6g
(0.33 g, 1.55 mmol) in 1 mL of dry acetone, afforded 8g as a
white solid (0.312 g, 84%). Rf 0.60 (hexane/EtOAc, 8:2). mp
94–95◦C (lit.[51] 95–96◦C).
To a solution of 7a (0.20 g, 1.61 mmol) in dry acetone (2 mL),
at room temperature and under a N2 atmosphere, anhydrous
K2CO3 (0.33 g, 2.4 mmol) was added. The mixture was stirred
at 60◦C for 40 min, and a solution of 6a (0.38 g, 1.91 mmol) in
dry acetone (1 mL) was added dropwise. The mixture was main-
tained under the same conditions for 12 h, was filtered, and the
solvent was removed under vacuum. The residue was purified
by column chromatography over silica gel (30 g, hexane/EtOAc,
95:5), to give 8a as a white solid (0.33 g, 84%). Rf 0.54 (hexane/
EtOAc, 8:2). mp 85–86◦C (lit.[48] 85–87◦C).
2-(3,5-Dimethoxyphenoxy)-1-(4-fluorophenyl)
ethanone 8h
Following the procedure as for 8a, with 7b (0.2 g, 1.3 mmol) in
2 mL of dry acetone, K2CO3 (0.26 g, 1.88 mmol), and 6h (0.34 g,
1.55 mmol) in 1 mL of dry acetone afforded 8h as a white solid
(0.33 g, 87%). Rf 0.50 (hexane/EtOAc, 8:2). mp 93–94◦C (lit.[51]
92–93◦C).
2-(3-Methoxyphenoxy)-1-(3-tolyl)ethanone 8b
Following the procedure as for 8a, with 7a (0.20 g, 1.61 mmol) in
2 mL of dry acetone, K2CO3 (0.33 g, 2.39 mmol), and 6b (0.41 g,
1.93 mmol) in 1 mL of dry acetone afforded 8b as a colourless
solid (0.34 g, 84%). Rf 0.56 (hexane/EtOAc, 8:2). mp 43–44◦C
(Found: C 75.2, H 6.4. C16H16O3 requires C 75.0, H 6.3%). νmax
(KBr)/cm−1 1704, 1611, 1493, 1433, 1334, 1270, 1202, 1151,
1036, 932, 833, 788, 752, 687. δH (CDCl3) 2.37 (3H, s, ArCH3),
3.71 (3H, s, OCH3), 5.19 (2H, s, OCH2), 6.47–6.53 (3H, m,
H2ꢀ, H4ꢀ, H6ꢀ), 7.09–7.17 (1H, m, H5ꢀ), 7.29–7.39 (2H, m, H4,
H5), 7.72–7.77 (2H, m, H2, H6). δC (CDCl3) 21.1, 55.0, 70.3,
101.2, 106.3, 107.0, 125.0, 128.2, 128.5, 129.7, 134.2, 134.4,
138.5, 159.0, 160.6, 194.1. m/z (EI) 256 (M+, 10%), 239 (5),
119 (100), 91 (18).
1-(4-Benzyloxy)-2-(3-methoxyphenoxy)ethanone 8i
Following the procedure as for 8a, with of 7a (0.5 g, 4.03 mmol)
in 5 mL of dry acetone, K2CO3 (0.83 g, 6.01 mmol), and 6f
(1.47 g, 4.82 mmol) in 1 mL of dry acetone afforded 8i as a white
solid (1.2 g, 86%). Rf 0.40 (hexane/EtOAc, 7:3). mp 96–97◦C
(Found: C 76.0, H 6.1. C22H20O4 requires C 75.8, H 5.8%). νmax
(KBr)/cm−1 1694, 1600, 1509, 1492, 1455, 1263, 1234, 1200,
1155, 1038, 975, 833, 740. δH (CDCl3) 3.74 (3H, s, OMe), 5.10
(2H, s, OCH2Ar), 5.16 (2H, s, H2), 6.46–6.54 (3H, m, H2ꢀ, H4ꢀ,
H6ꢀ), 6.98–7.04 (2H, m, H3), 7.11–7.19 (1H, m, H5ꢀ), 7.30–7.46
(5H, m, BnH), 7.93–7.99 (2H, m, H2). δC (CDCl3) 55.2, 70.0,
70.4, 101.3, 106.4, 107.1, 114.7, 127.4, 127.6, 128.2, 128.6,
129.9, 130.4, 135.9, 159.2, 160.7, 163.0, 192.8. m/z 348 (M+,
8%), 212 (14), 211 (100), 137 (4), 91 (87).
2-(3-Methoxyphenoxy)-1-(4-tolyl)ethanone 8c[49]
Following the procedure as for 8a, with 7a (0.20 g, 1.61 mmol) in
2 mL of dry acetone, K2CO3 (0.33 g, 2.39 mmol), and 6c (0.41 g,
1.93 mmol) in 1 mL of dry acetone afforded 8c as a white solid
(0.343 g, 83%). Rf 0.62 (hexane/EtOAc, 8:2). mp 70–71◦C.
Preparation of Enaminones 4a–i: (Z)-3-Dimethylamino-
2-(3-methoxyphenoxy)-1-phenylprop-2-en-1-one 4a
Under a N2 atmosphere, a mixture of of 8a (0.30 g, 1.24 mmol)
and DMFDMA (0.30 g, 2.48 mmol), in a threaded ACE glass
pressure tube with a sealed Teflon screw cap, was heated to
90◦C for 24 h. The crude product was purified by column chro-
matography over silica gel (35 g per g sample, hexane/EtOAc,
7:3) to give 4a as a pale yellow solid (0.325 g, 88%). Rf 0.39
(hexane/EtOAc, 1:1). mp 98–99◦C (Found: (M + H)+ 298.1450.
C18H20NO3 requires 298.1443). νmax (KBr)/cm−1 1651, 1588,
1568, 1489, 1438, 1324, 1282, 1149, 1133, 1118, 1042, 975, 835,
716. δH (CDCl3) 3.02 (6H, s, N(CH3)2), 3.76 (3H, s, OCH3),
1-(4-Fluorophenyl)-2-(3-methoxyphenoxy)ethanone 8d[50]
Following the procedure as for 8a, with 7a (0.20 g, 1.61 mmol) in
2 mL of dry acetone, K2CO3 (0.33 g, 2.39 mmol), and 6d (0.42 g,
1.93 mmol) in 1 mL of dry acetone afforded 8d as a white solid
(0.36 g, 86%). Rf 0.63 (hexane/EtOAc, 8:2). mp 61–62◦C.
2-(3-Methoxyphenoxy)-1-(3-methoxyphenyl)ethanone 8e
Following the procedure as for 8a, with 7a (0.20 g, 1.61 mmol) in
2 mL of dry acetone, K2CO3 (0.33 g, 2.39 mmol), and 6e (0.44 g,

Total Synthesis of 2-(4-Hydroxybenzyl)-6-methoxybenzofuran
995
6.49 (1H, br d, J 8.1, H4ꢀ or H6ꢀ), 6.52–6.62 (2H, m, H2ꢀ, H6ꢀ, or
H4ꢀ), 7.06 (1H, br s, HC=), 7.13 (1H, t, J 8.1, H5ꢀ), 7.30–7.39
(3H, m, H3, H4, H5), 7.58–7.68 (2H, m, H2, H6). δC (CDCl3)
44.0, 55.2, 101.4, 106.9, 107.3, 126.9, 127.9, 128.4, 129.9, 130.1,
139.8, 145.7, 160.0, 160.8, 189.1. m/z 297 (M+, 15%), 280 (33),
250 (14), 193 (18), 192 (100), 176 (26), 174 (76), 164 (85), 157
(56), 148 (23), 121 (21), 105 (26), 96 (15).
(KBr)/cm−1 1651, 1589, 1488, 1430, 1320, 1283, 1255, 1143,
1119, 1042, 761. δH (CDCl3) 3.03 (6H, s, N(CH3)2), 3.76 (3H,
s, OCH3), 3.80 (3H, s, OCH3), 6.49 (1H, br dd, J 8.0, 2.3, H4ꢀ or
H6ꢀ), 6.52–6.60 (2H, m, H2ꢀ, H6ꢀ, or H4ꢀ), 6.93 (1H, dm, J 7.5,
H4), 7.09 (1H, br s, HC=), 7.14 (1H, t, J 7.8, H5ꢀ), 7.15–7.29
(3H, m, H2, H5, H6). δC (CDCl3) 42.9, 55.2, 55.3, 101.4, 106.9,
107.3, 113.3, 116.2, 120.8, 126.7, 128.8, 129.9, 141.2, 145.5,
159.1, 160.0, 160.8, 188.7. m/z 327 (M+, 43%), 310 (34), 204
(51), 192 (100), 187 (60), 164 (63), 135 (66), 133 (37), 107 (36).
(Z)-3-Dimethylamino-2-(3-methoxyphenoxy)-
1-(3-tolyl)prop-2-en-1-one 4b
(Z)-2-(3,5-Dimethoxyphenoxy)-3-dimethylamino-
1-phenylprop-2-en-1-one 4f
Following the procedure as for 4a, with 8b (0.30 g, 1.17 mmol)
and DMFDMA (0.28 g, 2.34 mmol) afforded 4b as a brown oil
(0.31 g, 86%). Rf 0.51 (hexane/EtOAc, 1:1) (Found: (M + H)+
312.1602. C19H22NO3 requires 312.1600). νmax (KBr)/cm−1
1651, 1590, 1489, 1436, 1358, 1319, 1281, 1200, 1143, 1117,
1042, 758. δH (CDCl3) 2.35 (3H, br s, ArCH3), 3.01 (6H, s,
N(CH3)2), 3.76 (3H, s, OCH3), 6.48 (1H, ddd, J 8.1, 2.1, 0.9,
H4ꢀ or H6ꢀ), 6.52–6.60 (2H, m, H2ꢀ, H6ꢀ, or H4ꢀ), 7.03 (1H,
s, HC=), 7.13 (1H, t, J 8.1, H5ꢀ), 7.17–7.26 (2H, m, H5, H6),
7.38–7.42 (2H, m, H2, H4). δC (CDCl3) 21.3, 42.5, 55.2, 101.4,
106.9, 107.3, 125.4, 126.9, 127.6, 128.9, 129.9, 130.8, 137.6,
139.8, 145.0, 160.1, 160.8, 189.2. m/z 311 (M+, 37%), 294 (46),
192 (100), 188 (90), 171 (92), 164 (89), 162 (37), 121 (29), 119
(63), 91 (40).
Following the procedure as for 4a, with 8f (0.30 g, 1.1 mmol)
and DMFDMA (0.26 g, 2.2 mmol) afforded 4f as a brown oil
(0.32 g, 89%). Rf 0.31 (hexane/EtOAc, 1:1) (Found: (M + H)+
(FAB, 3NBA) 328.1541. C19H22NO4 requires 328.1549). νmax
(film)/cm−1 1651, 1596, 1474, 1430, 1324, 1204, 1152, 1126,
1062, 1004, 823, 702. δH (CDCl3) 3.03 (6H, s, N(CH3)2), 3.74
(6H, s, 2 OCH3), 6.07 (1H, br t, J 2.1, H4ꢀ), 6.16 (2H, br d, J 2.1,
H2ꢀ, H6ꢀ), 7.04 (1H, br s, HC=), 7.30–7.40 (3H, m, H3, H4, H5),
7.58–7.61 (2H, m, H2, H6). δC (CDCl3) 42.9, 55.3, 93.6, 93.9,
126.7, 127.9, 128.3, 130.0, 139.8, 145.7, 160.8, 161.5, 189.0.
m/z 327 (M+, 20%), 310 (28), 280 (18), 222 (100), 194 (82),
174 (33), 157 (26), 152 (20), 105 (39), 91 (13).
(Z)-3-Dimethylamino-2-(3-methoxyphenoxy)-
1-(4-tolyl)prop-2-en-1-one 4c
(Z)-2-(3,5-Dimethoxyphenoxy)-3-dimethylamino-
1-(4-tolyl)prop-2-en-1-one 4g
Following the procedure as for 4a, with 8c (0.30 g, 1.17 mmol)
and DMFDMA (0.28 g, 2.34 mmol) afforded 4c as a white solid
(0.31 g, 84%). Rf 0.43 (hexane/EtOAc, 1:1). mp 99–100◦C
(Found: (M + H)+ (FAB, m-nitrobenzyl alcohol (3NBA))
312.1605. C19H22NO3 requires 312.1600). νmax (KBr)/cm−1
1651, 1589, 1489, 1320, 1147, 1117, 1042, 975, 763. δH (CDCl3)
2.35 (3H, s,ArCH3), 3.02 (6H, s, N(CH3)2), 3.75 (3H, s, OCH3),
6.45–6.59 (3H, m, H2ꢀ, H4ꢀ, H6ꢀ), 7.07 (1H, br s, HC=), 7.08–
7.17 (3H, m, H5ꢀ, H3, H5), 7.52–7.59 (2H, m, H2, H6). δC
(CDCl3) 21.4, 42.0, 55.2, 101.3, 106.8, 107.3, 126.8, 128.51,
128.53, 129.9, 136.9, 140.4, 144.4, 160.1, 160.8, 188.9. m/z 311
(M+, 13%), 294 (26), 192 (66), 188 (75), 171 (100), 164 (87),
162 (26), 133 (19), 119 (32), 91 (18).
Following the procedure as for 4a, with 8g (0.30 g, 1.05 mmol)
and DMFDMA (0.25 g, 2.1 mmol) afforded 4g as a brown
solid (0.29 g, 82%). Rf 0.41 (hexane/EtOAc, 1:1). mp 88–89◦C
(Found: (M)+ 341.1638. C20H23NO4 requires 341.1627). νmax
(KBr)/cm−1 1650, 1614, 1578, 1477, 1438, 1360, 1317, 1196,
1154, 1115, 1062, 1009, 825, 759. δH (CDCl3) 2.35 (3H, s,
ArCH3), 3.02 (6H, s, N(CH3)2), 3.73 (6H, s, 2 OCH3), 6.06
(1H, t, J 2.1, H4ꢀ), 6.16 (2H, d, J 2.1, H2ꢀ, H6ꢀ), 7.06 (1H, br s,
HC=), 7.11–7.18 (2H, m, H3, H5), 7.51–7.58 (2H, m, H2, H6).
δC (CDCl3) 21.3, 42.5, 55.1, 93.5, 93.9, 126.7, 128.4, 128.5,
136.8, 140.2, 144.7, 160.8, 161.4, 188.7. m/z 341 (M+, 49%),
324 (56), 294 (19), 281 (21), 222 (91), 194 (96), 171 (66), 162
(52), 119 (100), 91 (33).
(Z)-3-Dimethylamino-1-(4-fluorophenyl)-
2-(3-methoxyphenoxy)prop-2-en-1-one 4d
(Z)-2-(3,5-Dimethoxyphenoxy)-1-(4-fluorophenyl)-
3-dimethylaminoprop-2-en-1-one 4h
Following the procedure as for 4a, with 8d (0.30 g, 1.15 mmol)
and DMFDMA (0.27 g, 2.30 mmol) afforded 4d as a pale brown
solid (0.33 g, 91%). Rf 0.46 (hexane/EtOAc, 1:1). mp 84–85◦C
(Found: (M + H)+ 316.1348. C18H19NO3F requires 316.1349).
νmax (KBr)/cm−1 1651, 1601, 1489, 1432, 1321, 1283, 1229,
1149, 1119, 1042, 845, 765. δH (CDCl3) 3.05 (6H, s, N(CH3)2),
3.75 (3H, s, OCH3), 6.44–6.55 (3H, m, H2ꢀ, H4ꢀ, H6ꢀ), 6.94–7.04
(2H, m, H3), 7.12 (1H, t, J 7.8, H5ꢀ), 7.16 (1H, br s, HC=), 7.65–
7.74 (2H, m, H2). δC (CDCl3) 42.5, 55.1, 101.3, 106.8, 107.2,
114.7, 126.4, 129.9, 130.6, 135.6, 144.1, 159.9, 160.8, 163.8,
187.6. m/z 315 (M+, 15%), 298 (18), 192 (100), 175 (40), 164
(66), 135 (36), 123 (48), 121 (26), 95 (15).
Following the procedure as for 4a, with 8h (0.25 g, 0.86 mmol)
and DMFDMA (0.205 g, 1.72 mmol) afforded 4h as a pale
brown oil (0.278 g, 93%). Rf 0.32 (hexane/EtOAc, 1:1) (Found:
(M + H)+ (FAB, 3NBA) 346.1460. C19H21NO4F requires
346.1455). νmax (film)/cm−1 1652, 1599, 1474, 1429, 1320,
1230, 1204, 1153, 1124, 1055, 823, 766. δH (CDCl3) 3.04 (6H,
s, N(CH3)2), 3.72 (6H, s, OCH3), 6.05 (1H, t, J 2.1, H4ꢀ), 6.11
(2H, d, J 2.1, H2ꢀ, H6ꢀ), 6.95–7.05 (2H, m, H3, H5), 7.14 (1H,
br s, HC=), 7.64–7.72 (2H, m, H2, H6). δC (CDCl3) 44.0, 55.3,
93.6, 94.0, 114.8, 126.5, 130.6, 135.6, 144.1, 160.8, 161.5, 163.9,
187.7. m/z 345 (M+, 30%), 328 (28), 222 (93), 194 (100), 191
(47), 163 (34), 152 (42), 123 (84), 109 (14), 95 (21).
(Z)-3-Dimethylamino-2-(3-methoxyphenoxy)-
1-(3-methoxyphenyl)prop-2-en-1-one 4e
(Z)-1-(4-Benzyloxyphenyl)-3-dimethylamino-
2-(3-methoxyphenoxy)prop-2-en-1-one 4i
Following the procedure as for 4a, with 8e (0.30 g, 1.10 mmol)
and DMFDMA (0.26 g, 2.20 mmol) afforded 4e as a brown oil
(0.288 g, 80%). Rf 0.35 (hexane/EtOAc, 1:1) (Found: (M + H)+
(FAB, 3NBA) 328.1547. C19H22NO4 requires 328.1549). νmax
Following the procedure as for 4a, with 8i (0.50 g, 1.44 mmol)
and DMFDMA (0.34 g, 2.86 mmol) afforded 4i as a pale yellow
oil (0.47 g, 81%). Rf 0.21 (hexane/EtOAc, 1:1) (Found: C 74.2,
H 6.4, N 3.3. C25H25NO4 requires C 74.4, H 6.3, N 3.5%). νmax

996
C. Correa et al.
(film)/cm−1 1651, 1601, 1489, 1319, 1231, 1172, 1148, 1116,
1040, 840, 766. δH (CDCl3) 3.02 (6H, s, NMe2), 3.74 (3H, s,
OCH3), 5.06 (2H, s, OCH2PH), 6.46 (1H, ddd, J 8.1, 2.1, 0.6,
H4ꢀ or H6ꢀ), 6.50–6.57 (2H, m, H2, H6ꢀ or H4ꢀ), 6.80–6.94 (2H,
m, H3), 7.11 (1H, t, J 8.1, H5ꢀ), 7.13 (1H, br s, HC=), 7.30–7.44
(5H, m, ArH), 7.67–7.73 (2H, m, H2). δC (CDCl3) 42.0, 55.2,
69.9, 101.3, 106.8, 107.3, 114.0, 126.7, 127.4, 128.0, 128.5,
129.9, 130.5, 132.2, 136.5, 143.7, 160.1, 160.5, 160.8, 188. m/z
403 (M+, 18%), 386 (15), 280 (58), 263 (43), 239 (23), 211 (42),
172 (60), 164 (100), 121 (25), 91 (98).
(0.13 g, 76%). Rf 0.52 (hexane/EtOAc, 8:2). mp 158–159◦C.
νmax (KBr)/cm−1 1635, 1599, 1502, 1343, 1303, 1272, 1220,
1156, 1133, 1118, 1100, 1027, 880, 843, 820, 762. δH (CDCl3)
3.90 (3H, s, OCH3), 6.97 (1H, dd, J 8.7, 2.3, H5), 7.10 (1H, br
d, J 2.3, H7), 7.17–7.25 (2H, m, H3ꢀ, H5ꢀ), 7.48 (1H, d, J 0.9,
H3), 7.58 (1H, d, J 8.7, H4), 8.05–8.12 (2H, m, H2ꢀ, H6ꢀ). δC
(CDCl3) 55.7, 95.6, 114.6, 115.7, 117.0, 120.3, 123.6, 131.9,
133.6, 151.8, 157.6, 161.3, 165.5, 182.2. m/z 270 (M+, 100%),
255 (22), 227 (94), 199 (30), 175 (59), 171 (32).
6-Methoxy-2-(3-methoxybenzoyl)benzofuran 2e
General Procedure for the Preparation
of 2-Benzoylbenzofurans 2a–i: 2-Benzoyl-
6-methoxybenzofuran 2a
Following the procedure as for 2a, with 4e (0.20 g, 0.61 mmol)
and ZnCl2 (0.41 g, 3.01 mmol) afforded 2e as a pale orange
oil (0.095 g, 55%). Rf 0.31 (hexane/EtOAc, 8:2) (Found: (M)+
(FAB, 3NBA) 282.0897. C17H14O4 requires 282.0892). νmax
(film)/cm−1 1644, 1619, 1542, 1494, 1269, 1219, 1154, 1113,
986, 756. δH (CDCl3) 3.88 (6H, s, OCH3), 6.95 (1H, dd, J 8.9,
2.3, H5), 7.08 (1H, br d, J 1.8, H7), 7.15 (1H, ddd, J 8.1, 2.7,
0.9, H4ꢀ), 7.42 (1H, t, J 8.1, H5ꢀ), 7.46 (1H, d, J 0.9, H3), 7.50
(1H, dd, J 2.7, 1.8, H2ꢀ), 7.56 (1H, d, J 8.9, H4), 7.59 (1H, ddd,
J 8.1, 1.8, 0.9, H6ꢀ). δC (CDCl3) 55.4, 55.6, 95.5, 113.7, 114.4,
117.4, 118.8, 120.2, 121.7, 123.6, 129.4, 138.6, 151.6, 157.5,
159.5, 161.1, 183.5. m/z 282 (M+, 100%), 267 (13), 251 (46),
239 (95), 223 (17), 175 (64), 135 (29), 119 (50), 107 (23).
Under a N2 atmosphere at room temperature, a mixture of
4a (0.20 g, 0.67 mmol) and ZnCl2 (0.46 g, 3.38 mmol) in dry
CH2Cl2 (80 mL) was stirred at room temperature for 72 h.
The mixture was filtered, washed with H2O (2 × 20 mL), dried
(Na2SO4), and the solvent was removed under vacuum. The
residue was purified by column chromatography over silica gel
(25 g, hexane/EtOAc, 9:1) to give 2a as a white solid (0.122 g,
72%). Rf 0.46 (hexane/EtOAc, 8:2). mp 104–105◦C (lit.[16]
105◦C). νmax (KBr)/cm−1 1644, 1619, 1542, 1494, 1266, 1228,
1153, 1112, 1026, 976, 823, 722, 697. δH (CDCl3) 3.85 (3H, s,
OCH3), 6.92 (1H, dd, J 8.4, 2.1, H5), 7.06 (1H, br d, J 2.1, H7),
7.42 (1H, d, J 0.9, H3), 7.45–7.54 (3H, m, H4, H3ꢀ, H5ꢀ), 7.54–
7.62 (1H, m, H4ꢀ), 7.94–8.00 (2H, m, H2ꢀ, H6ꢀ). δC (CDCl3)
55.7, 95.5, 114.5, 117.4, 120.3, 123.6, 128.4, 129.2, 132.6, 137.5,
151.7, 157.6, 161.2, 183.9. m/z 252 (M+, 89%), 209 (100), 181
(22), 175 (60), 153 (26), 119 (41), 105 (28), 77 (16).
2-(Benzoyl)-4,6-dimethoxybenzofuran 2f
Following the procedure as for 2a, with 4f (0.20 g, 0.612 mmol)
and ZnCl2 (0.42 g, 3.06 mmol) afforded 2f as a pale green solid
(0.135 g, 78%). Rf 0.36 (hexane/EtOAc, 8:2). mp 140–141◦C
(lit.[48] 140–141◦C). νmax (film)/cm−1 1639, 1618, 1539, 1504,
1281, 1220, 1155, 1132, 1039, 967, 821, 724. δH (CDCl3) 3.88
(3H, s, OCH3), 3.91 (3H, s, OCH3), 6.33 (1H, d, J 1.8, H5),
6.70 (1H, br s, H7), 7.44–7.55 (3H, m, H3, H3ꢀ, H5ꢀ), 7.57–7.65
(1H, m, H4ꢀ), 7.94–8.00 (2H, m, H2ꢀ, H6ꢀ). δC (CDCl3) 55.5,
55.7, 87.9, 95.1, 112.1, 115.5, 128.3, 129.1, 132.3, 137.6, 150.4,
155.2, 158.3, 162.7, 183.5. m/z 282 (M+, 93%), 267 (20), 239
(70), 211 (33), 205 (38), 149 (36), 105 (100), 77 (18).
6-Methoxy-2-(3-methylbenzoyl)benzofuran 2b
Following the procedure as for 2a, with 4b (0.20 g, 0.64 mmol)
and ZnCl2 (0.43 g, 3.16 mmol) afforded 2b as a white solid
(0.121 g, 71%). Rf 0.51 (hexane/EtOAc, 8:2). mp 83–84◦C
(Found: (M + H)+ (FAB, 3NBA) 267.1021. C17H15O3 requires
267.1021). νmax (KBr)/cm−1 1644, 1619, 1542, 1494, 1268,
1165, 1112, 1025, 980, 845, 751, 736. δH (CDCl3) 2.45 (3H,
s, ArCH3), 3.89 (3H, s, OCH3), 6.95 (1H, dd, J 8.7, 2.1, H5),
7.10 (1H, br d, J 2.1, H7), 7.37–7.43 (2H, m, H4ꢀ, H5ꢀ), 7.44 (1H,
d, J 0.9, H3), 7.57 (1H, d, J 8.7, H4), 7.75–7.81 (2H, m, H2ꢀ,
H6ꢀ). δC (CDCl3) 21.3, 55.6, 95.5, 114.4, 117.3, 120.2, 123.6,
126.4, 128.2, 129.6, 133.3, 137.4, 138.3, 151.7, 157.5, 161.1,
184.1. m/z 266 (M+, 68%), 251 (37), 223 (90), 195 (14), 175
(66), 152 (14), 119 (100), 91 (30).
4,6-Dimethoxy-2-(4-methylbenzoyl)benzofuran 2g
Following the procedure as for 2a, with 4g (0.20 g, 0.587 mmol)
and ZnCl2 (0.40 g, 2.93 mmol) afforded 2g as a pale green solid
(0.113 g, 65%). Rf 0.39 (hexane/EtOAc, 8:2). mp 126–127◦C
(Found: (M + H)+ (FAB, 3NBA) 297.1118. C18H17O4 requires
297.1127). νmax (KBr)/cm−1 1648, 1615, 1547, 1489, 1265,
1233, 1191, 1151, 1120, 1108, 1027, 977, 828, 806, 756. δH
(CDCl3) 2.46 (3H, s, ArCH3), 3.88 (3H, s, OCH3), 3.91 (3H, s,
OCH3), 6.33 (1H, d, J 1.8, H5), 6.71 (1H, dd, J 1.8, 0.9, H7),
7.28–7.34 (2H, m, H3ꢀ, H5ꢀ), 7.51 (1H, d, J 0.9, H3), 7.84–7.92
(2H, m, H2ꢀ, H6ꢀ). δC (CDCl3) 21.5, 55.5, 55.7, 87.9, 95.1, 112.0,
115.0, 129.0, 129.2, 134.8, 143.1, 150.5, 155.1, 158.1, 162.5,
183.1. m/z 296 (M+, 100%), 281 (26), 253 (97), 225 (24), 205
(18), 149 (20), 119 (76), 91 (21).
6-Methoxy-2-(4-methylbenzoyl)benzofuran 2c[20]
Following the procedure as for 2a, with 4c (0.20 g, 0.64 mmol)
and ZnCl2 (0.43 g, 3.16 mmol) afforded 2c as a white solid
(0.109 g, 64%). Rf 0.50 (hexane/EtOAc, 8:2). mp 135–136◦C.
νmax (film)/cm−1 1647, 1615, 1542, 1491, 1268, 1233, 1173,
1152, 1131, 1110, 1029, 974, 807, 756. δH (CDCl3) 2.46 (3H, s,
ArCH3), 3.89 (3H, s, OCH3), 6.95 (1H, dd, J 8.7, 2.1, H5), 7.10
(1H, br d, J 2.1, H7), 7.28–7.35 (2H, m, H3ꢀ, H5ꢀ), 7.45 (1H, d,
J 0.9, H3), 7.56 (1H, d, J 8.7, H4), 7.89–7.95 (2H, m, H2ꢀ, H6ꢀ).
δC (CDCl3) 21.7, 55.7, 95.6, 114.4, 116.9, 120.3, 123.5, 129.1,
129.4, 134.8, 143.4, 151.9, 157.5, 161.0, 183.6. m/z 266 (M+,
85%), 251 (42), 223 (90), 195 (15), 175 (36), 119 (100), 91 (34).
2-(4-Fluorobenzoyl)-4,6-dimethoxybenzofuran 2h
Following the procedure as for 2a, with 4h (0.20 g, 0.58 mmol)
and ZnCl2 (0.39 g, 2.9 mmol) afforded 2h as a white solid
(0.14 g, 78%). Rf 0.41 (hexane/EtOAc, 8:2). mp 129–130◦C
(Found: (M + H)+ (FAB, 3NBA) 301.0879. C17H14FO4 requires
301.0876). νmax (KBr)/cm−1 1642, 1619, 1600, 1539, 1503,
1297, 1280, 1221, 1201, 1156, 1133, 762. δH (CDCl3) 3.88 (3H,
s, OCH3), 3.91 (3H, s, OCH3), 6.33 (1H, d, J 1.8, H5), 6.69 (1H,
dd, J 1.8, 0.6, H7), 7.15–7.23 (2H, m, H3ꢀ), 7.52 (1H, d, J 0.6,
2-(4-Fluorobenzoyl)-6-methoxybenzofuran 2d[20]
Following the procedure as for 2a, with 4d (0.20 g, 0.635 mmol)
and ZnCl2 (0.43 g, 3.16 mmol) afforded 2d as a white solid

Total Synthesis of 2-(4-Hydroxybenzyl)-6-methoxybenzofuran
997
H3), 8.00–8.07 (2H, m, H2ꢀ). δC (CDCl3) 55.6, 55.8, 87.9, 95.3,
112.1, 115.3, 115.5, 131.7, 133.8, 150.3, 155.2, 158.3, 162.8,
165.3, 181.8. m/z 300 (M+, 70%), 285 (17), 257 (47), 229 (17),
205 (19), 123 (100), 95 (14).
afforded 3c as a colourless oil (0.086 g, 91%). Rf 0.52 (hexane/
EtOAc, 9:1) (Found: (M+) 252.1125. C17H16O2 requires
252.1150). νmax (film)/cm−1 1621, 1594, 1501, 1454, 1435,
1419, 1219, 1200, 1156, 1128, 1001, 814. δH (CDCl3) 2.32 (3H,
s, ArCH3), 3.80 (3H, s, OCH3), 4.02 (2H, s, CH2Ar), 6.26–6.28
(1H, m, H3), 6.80 (1H, dd, J 8.7, 2.3, H5), 6.95 (1H, br d, J 2.3,
H7), 7.08–7.20 (4H, m,ArH), 7.30 (1H, d, J 8.7, H4). δC (CDCl3)
21.0, 34.5, 55.7, 95.9, 102.8, 111.2, 120.3, 122.1, 128.7, 129.2,
134.4, 136.2, 155.8, 157.0, 157.3. m/z 252 (M+, 100%), 251
(55), 237 (43), 209 (18), 165 (28), 161 (60).
2-(4-Benzyloxybenzoyl)-6-methoxybenzofuran 2i
Following the procedure as for 2a, with 4i (0.20 g, 0.49 mmol)
and ZnCl2 (0.2 g, 1.47 mmol), and stirring the reaction mixture
for 48 h, afforded 2i as a white solid (0.12 g, 68%). Rf 0.49
(hexane/EtOAc, 7:3). mp 135–136◦C (Found: C 76.9, H 5.0.
C23H18O4 requires C 77.1, H 5.1%). νmax (film)/cm−1 1633,
1602, 1543, 1494, 1455, 1384, 1302, 1256, 1235, 1154, 1113,
1024, 978, 760, 740. δH (CDCl3) 3.89 (3H, s, OCH3), 5.17 (2H,
s, OCH2PH), 6.96 (1H, dd, J 8.7, 2.1, H5), 7.05–7.10 (2H, m,
H3ꢀ), 7.10 (1H, br s, H7), 7.35–7.48 (5H, m, ArH), 7.46 (1H,
d, J 0.9, H3), 7.57 (1H, d, J 8.7, H4), 8.04–8.09 (2H, m, H2ꢀ).
δC (CDCl3) 55.7, 70.1, 95.6, 114.3, 114.6, 116.3, 120.3, 123.5,
127.5, 128.2, 128.7, 130.3, 131.7, 136.1, 152.1, 157.4, 160.9,
162.5, 182.4. m/z (EI) 358 (M+, 30%), 267 (1), 253 (1), 238
(82), 211 (11), 196 (5), 91 (100).
2-(4-Fluorobenzyl)-6-methoxybenzofuran 3d
Following the procedure as for 3a, with 2d (0.10 g, 0.37 mmol),
N2H4 (0.077 g, 2.41 mmol), and KOH (0.135 g, 2.41 mmol)
afforded 3d as a colourless oil (0.082 g, 78%). Rf 0.63 (hexane/
EtOAc, 9:1) (Found: (M + H)+ (FAB, 3NBA) 257.0975.
C16H14O2F requires 257.0978). νmax (film)/cm−1 1627, 1588,
1509, 1492, 1439, 1222, 1193, 1291, 1150, 1107, 1029, 960, 822.
δH (CDCl3) 3.80 (3H, s, OCH3), 4.09 (2H, s, CH2Ar), 6.43–6.45
(1H, m, H3), 6.82 (1H, dd, J 8.9, 2.3, H5), 7.02 (1H, br d, J 2.3,
H7), 7.05–7.14 (2H, m, H3ꢀ, H5ꢀ), 7.31–7.40 (3H, m, H4, H2ꢀ,
H6ꢀ). δC (CDCl3) 34.2, 55.8, 96.3, 103.7, 112.2, 115.9, 121.4,
122.7, 131.4, 134.8, 156.7, 157.5, 158.5, 162.5. m/z 256 (M+,
70%), 241 (9), 213 (21), 183 (20), 165 (48), 161 (100), 123 (14).
General Procedure for the Preparation of
2-Benzylbenzofurans 3a–i. 2-Benzyl-
6-methoxybenzofuran 3a
Under a N2 atmosphere, a mixture of 2a (0.1 g, 0.4 mmol) in
ethylene glycol (1 mL) and dry N2H4 (0.083 g, 2.59 mmol) was
stirred at 150◦C for 15 min.At room temperature, KOH (0.145 g,
2.59 mmol) was added and the mixture was heated to 150◦C
for 4 h. A 2% aqueous solution of HCl was added until neu-
tral, and the mixture was washed with CH2Cl2 (2 × 20 mL) and
dried (Na2SO4), and the solvent was removed under vacuum.
The residue was purified by column chromatography over silica
gel (30 g, hexane/EtOAc, 9:1) to give 3a as a pale yellow oil
(0.084 g, 89%). Rf 0.60 (hexane/EtOAc, 9:1) (Found: (M + H)+
(FAB, 3NBA) 239.1069. C16H15O2 requires 239.1072). νmax
(film)/cm−1 1627, 1587, 1492, 1439, 1291, 1149, 1107, 1029,
961, 824, 705. δH (CDCl3) 3.80 (3H, s, OCH3), 4.06 (2H, br
s, CH2Ph), 6.28–6.31 (1H, m, H3), 6.80 (1H, dd, J 8.4, 2.4,
H5), 6.95 (1H, br d, J 2.4, H7), 7.20–7.36 (6H, m, H4, ArH).
δC (CDCl3) 34.9, 55.7, 95.9, 103.0, 111.2, 120.4, 122.0, 126.7,
128.6, 128.8, 137.4, 155.9, 156.7, 157.3. m/z 238 (M+, 100%),
195 (22), 165 (25), 161 (88), 105 (10).
2-(3-Methoxybenzyl)-6-methoxybenzofuran 3e
Following the procedure as for 3a, with 2e (0.10 g, 0.355 mmol),
N2H4 (0.074 g, 2.30 mmol), and KOH (0.123 g, 2.3 mmol)
afforded 3e as a colourless oil (0.086 g, 90%). Rf 0.45 (hexane/
EtOAc, 9:1) (Found: (M + H)+ (FAB, 3NBA) 269.1184.
C17H17O3 requires 269.1178). νmax (film)/cm−1 1625, 1587,
1491, 1438, 1289, 1261, 1149, 1107, 960, 822. δH (CDCl3) 3.78
(3H, s, OCH3), 3.81 (3H, s, OCH3), 4.04 (2H, s, CH2Ar), 6.30–
6.33 (1H, m, H3), 6.77–6.81 (1H, m, H4ꢀ), 6.82 (1H, dd, J 8.7,
2.4, H5), 6.83–6.85 (1H, m, H2ꢀ), 6.88 (1H, br d, J 7.8, H6ꢀ),
6.96 (1H, br d, J 2.4, H7), 7.23 (1H, t, J 7.8, H5ꢀ), 7.32 (1H, d, J
8.7, H4). δC (CDCl3) 34.9, 55.1, 55.7, 95.9, 103.1, 111.2, 112.0,
114.6, 120.4, 121.2, 122.0, 129.5, 139.0, 155.8, 156.5, 157.3,
159.7. m/z (EI) 268 (M+, 67%), 253 (19), 237 (31), 225 (17),
165 (25), 161 (100), 118 (9).
2-(Benzyl)-4,6-dimethoxybenzofuran 3f
Following the procedure as for 3a, with 2f (0.10 g, 0.355 mmol),
N2H4 (0.074 g, 2.3 mmol), and KOH (0.123 g, 2.3 mmol)
afforded 3f as a white solid (0.084 g, 88%). Rf 0.5 (hexane/
EtOAc, 9:1). mp 73–74◦C (Found: (M + H)+ (FAB, 3NBA)
269.1168. C17H17O3 requires 269.1178). νmax (film)/cm−1
1621, 1592, 1502, 1454, 1435, 1420, 1219, 1200, 1155, 1127,
1101, 816, 701. δH (CDCl3) 3.80 (3H, s, OCH3), 3.86 (3H, s,
OCH3), 4.05 (2H, s, CH2Ar), 6.28 (1H, d, J 1.8, H5), 6.36–6.39
(1H, m, H3), 6.58–6.60 (1H, m, H7), 7.20–7.34 (5H, m, BnH).
δC (CDCl3) 34.9, 55.5, 55.7, 88.2, 93.9, 100.5, 112.3, 126.6,
128.5, 128.8, 137.5, 152.9, 155.1, 156.5, 158.4. m/z 268 (M+,
100%), 253 (12), 191 (86), 165 (34), 105 (23).
2-(3-Methylbenzyl)-6-methoxybenzofuran 3b
Following the procedure as for 3a, with 2b (0.10 g, 0.38 mmol),
N2H4 (0.079 g, 2.47 mmol), and KOH (0.138 g, 2.47 mmol)
afforded 3b as a colourless oil (0.085 g, 90%). Rf 0.61 (hexane/
EtOAc, 9:1) (Found: (M + H)+ (FAB, 3NBA) 253.1232.
C17H17O2 requires 253.1229). νmax (film)/cm−1 1625, 1588,
1491, 1438, 1289, 1149, 1106, 1028, 820. δH (CDCl3) 2.33 (3H,
s, ArCH3), 3.81 (3H, s, OCH3), 4.03 (2H, s, CH2Ar), 6.29–6.31
(1H, m, H3), 6.81 (1H, dd, J 8.6, 2.4, H5), 6.96 (1H, br d, J 2.4,
H7), 7.03–7.12 (3H, m, H2ꢀ, H4ꢀ, H6ꢀ), 7.17–7.24 (1H, m, H5ꢀ),
7.32 (1H, d, J 8.6, H4). δC (CDCl3) 21.4, 34.9, 55.7, 95.9, 102.9,
111.2, 120.4, 122.0, 125.9, 127.4, 128.4, 129.6, 137.3, 138.2,
155.8, 156.9, 157.3. m/z 252 (M+, 100%), 237 (36), 209 (18),
165 (27), 161 (94), 119 (11).
2-(4-Methylbenzyl)-4,6-dimethoxybenzofuran 3g
Following the procedure as for 3a, with 2g (0.10 g, 0.34 mmol),
N2H4 (0.071 g, 2.21 mmol), and KOH (0.124 g, 2.21 mmol)
afforded 3g as a white solid (0.085 g, 90%). Rf 0.65 (hexane/
EtOAc, 9:1). mp 56–57◦C (Found: (M + H)+ (FAB, 3NBA)
283.1335. C18H19O3 requires 283.1334). νmax (KBr)/cm−1
1624, 1588, 1491, 1439, 1290, 1189, 1153, 1105, 1025, 938,
2-(4-Methylbenzyl)-6-methoxybenzofuran 3c
Following the procedure as for 3a, with 2c (0.10 g, 0.38 mmol),
N2H4 (0.079 g, 2.47 mmol), and KOH (0.138 g, 2.47 mmol)

998
C. Correa et al.
816. δH (CDCl3) 2.32 (3H, s, ArCH3), 3.79 (3H, s, OCH3),
3.85 (3H, s, OCH3), 4.00 (2H, s, CH2Ar), 6.27 (1H, d, J 2.0,
H5), 6.35–6.36 (1H, m, H3), 6.58 (1H, dd, J 2.0, 0.9, H7),
7.07–7.19 (4H, m, ArH). δC (CDCl3) 21.0, 34.4, 55.4, 55.7,
88.2, 93.9, 100.3, 112.3, 128.7, 129.2, 134.4, 136.1, 152.9, 155.4,
156.5, 158.3. m/z 282 (M+, 100%), 267 (35), 191 (65), 179 (18),
119 (20).
chromatography over silica gel (10 g, hexane/EtOAc, 9:1) to give
1 as a pale yellow oil (0.024 g, 68%).
Method C
At 0◦C and under a N2 atmosphere, BF3·OEt2 (0.224 g,
1.58 mmol) was added to a solution of triethylsilane (0.42 g,
3.62 mmol) in CH2Cl2 (10 mL). After stirring for 10 min, 2i
(0.05 g, 0.14 mmol) in CH2Cl2 (2 mL) was added dropwise,
and the mixture was stirred at 0◦C for 1 h, then at room tem-
perature for 3 h. The mixture was poured into a cold aqueous
saturated solution of NaCl (20 mL). The aqueous layer was
washed with CH2Cl2 (2 × 10 mL), the combined organic lay-
ers were dried (Na2SO4), and the solvent was removed under
vacuum. The residue was purified by column chromatography
over silica gel (10 g, hexane/EtOAc, 9:1) to give 1 as a pale yel-
low oil (0.014 g, 40%). Rf 0.27 (hexane/EtOAc, 8:2) (Found:
(M+) (FAB, 3NBA) 254.0948. C16H14O3 requires 254.0943).
νmax (film)/cm−1 3420, 2929, 1707, 1616, 1515, 1492, 1441,
1271, 1194, 1149, 1107, 1028, 822. δH (CDCl3) 3.83 (3H, s,
OCH3), 4.00 (2H, br s, CH2Ph), 6.26–6.28 (1H, m, H3), 6.77–
6.81 (2H, m, H4ꢀ, H6ꢀ), 6.81 (1H, dd, J 8.4, 2.2, H5), 6.96 (1H,
br d, J 2.2, H7), 7.12–7.18 (2H, m, H3ꢀ, H7ꢀ), 7.32 (1H, d, J 8.4,
H4). δC (CDCl3) 34.1, 55.7, 95.9, 102.8, 111.2, 115.4, 120.4,
122.0, 129.0, 130.0, 154.3, 155.8, 157.2, 157.3. m/z 254 (M+,
4%), 210 (23), 181 (22), 167 (85), 165 (75), 161 (100), 149 (73),
118 (14), 105 (13), 77 (24).
2-(4-Fluorobenzyl)-4,6-dimethoxybenzofuran 3h
Following the procedure as for 3a, with 2h (0.10 g, 0.33 mmol),
N2H4 (0.069 g, 2.15 mmol), and KOH (0.12 g, 2.66 mmol)
afforded 3h as a pale yellow oil (0.072 g, 75%). Rf 0.62 (hexane/
EtOAc, 9:1) (Found: (M + H)+ (FAB, 3NBA) 287.1086.
C17H16O3F requires 287.1083). νmax (film)/cm−1 1620, 1503,
1455, 1419, 1219, 1200, 1155, 1127, 1101, 1043, 816. δH
(CDCl3) 3.79 (3H, s, OCH3), 3.85 (3H, s, OCH3), 4.00 (2H,
s, CH2Ar), 6.28 (1H, d, J 2.1, H5), 6.36 (1H, d, J 0.9, H3), 6.58
(1H, dd, J 2.1, 0.9, H7), 6.94–7.03 (2H, m, H3ꢀ, H5ꢀ), 7.18–
7.28 (2H, m, H2ꢀ, H6ꢀ). δC (CDCl3) 34.0, 55.5, 55.7, 88.2, 93.9,
100.5, 112.2, 115.2, 130.2, 133.2, 153.0, 154.8, 156.6, 158.5,
161.7. m/z 286 (M+, 100%), 271 (14), 255 (13), 191 (94), 183
(34), 123 (27).
2-(4-Benzyloxybenzyl)-6-methoxybenzofuran 3i
A mixture of Zn–Hg (1.50 g, 5.64 mmol) and HCl (36%; 1 mL)
was heated to 65◦C, and 2i (0.05 g, 0.14 mmol) in EtOH (1 mL)
and HCl (36%; 2 mL) was added dropwise. The mixture was
stirred for 8 h and washed with CH2Cl2 (5 × 10 mL).The organic
layer was washed with a 5% aqueous solution of NaHCO3 until
neutral, dried (Na2SO4), and the solvent was removed under
vacuum. The residue was purified by column chromatography
over silica gel (5 g, hexane/EtOAc, 9:1) to give 3i as a colour-
less oil (0.039 g, 81%). Rf 0.64 (hexane/EtOAc, 8:2) (Found:
(M+) (FAB, 3NBA) 344.1407. C23H20O3 requires 344.1412).
νmax (film)/cm−1 1623, 1509, 1491, 1440, 1384, 1149, 1026. δH
(CDCl3) 3.82 (3H, s, OCH3), 4.01 (2H, s, CH2Ar), 5.05 (2H,
s, OCH2Ph), 6.28 (1H, br s, H3), 6.81 (1H, dd, J 8.7, 2.4, H5),
6.92–6.95 (2H, m, H3ꢀ), 6.96 (1H, br d, J 1.5, H7), 7.18–7.24
(2H, m, H2ꢀ), 7.32 (1H, d, J 8.7, H4), 7.32–7.45 (5H, m, BnH).
δC (CDCl3) 34.1, 55.7, 70.0, 95.9, 102.8, 111.2, 114.9, 120.4,
122.0, 127.5, 127.9, 128.6, 129.7, 129.8, 137.0, 155.8, 157.1,
157.2, 157.6. m/z 344 (M+, 10%), 253 (25), 237 (8), 211 (100),
137 (4), 91 (82).
Acknowledgements
We thank Dr Eleuterio Burgueño for his help in spectrometric measure-
ments, andAlan Larsen for reviewing the English in the manuscript. M.C.C.
and J.T. gratefully acknowledge Secretaría de Investigación y Posgrado del
IPN (grants 20060583, 20070339, and 20080527; 20060371, 20070055,
and 20080385), and CONACYT (grants 43508-Q and 83446) for finan-
cial support. C.C. and F.J. thank CONACYT for graduate scholarships
(202216, 170116). M.C.C., L.G.Z. and J.T. are fellows of the EDI-IPN and
COFAA-IPN programs.
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