A controlled synthesis of nature-mimicking benzofurans and their corresponding dimers

Article abstract of DOI:10.1055/s-2006-944194

Benzofurans functionalized with hydroxy and acetyl functionalities are not only the core structures found in a large number of biologically important natural products, but also the vital precursors for several naturally occurring furanoflavonoids. Numerou

Full text of DOI:10.1055/s-2006-944194

LETTER
1497
A Controlled Synthesis of Nature-Mimicking Benzofurans and their
Corresponding Dimers1
Synthesis of
N
aturally-
a
Mimicking
n
Benzofuran
i
sh Dixit,a Ashoke Sharon,b Prakas R. Maulik,b Atul Goel*a
a
Medicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: agoel13@yahoo.com
b
Molecular & Structural Biology, Central Drug Research Institute, Lucknow 226001, India
Received 22 March 2006
functionality but differ in their point of attachments. For
example, euparin possessed a 5-acetyl-6-hydroxybenzo-
furan skeleton, while ageratone possessed a 6-acetyl-5-
hydroxybenzofuran ring system. Similarly, 4(6)-hydroxy-
Abstract: Benzofurans functionalized with hydroxy and acetyl
functionalities are not only the core structures found in a large num-
ber of biologically important natural products, but also the vital pre-
cursors for several naturally occurring furanoflavonoids. Numerous
synthetic methodologies are available in the literature for the tremetone possessed 5-acetyl-4(6)-hydroxy-2,3-dihydro-
synthesis of functionalized benzofurans but access to benzofurans
benzofuran architecture, while viscidone possessed 6-
with adjacent hydroxy and acetyl functionalities shows paucity of
acetyl-5-hydroxy-2,3-dihydrobenzofuran ring system.
references. In this paper we report highly convenient synthesis of
These positional isomeric core structures present real
nature-mimicking benzofurans and their dimers from easily acces-
challenges to natural product chemists in assigning the
sible precursors.
correct structure for an unknown compound. In addition,
Key words: benzofuran, dihydrobenzofuran, benzofuran dimer,
these benzofurans with an adjacent hydroxy and acetyl
Amberlyst 15, bibenzofuran
functionality are key precursors for the synthesis of
several naturally occurring angular and linear furano-
flavonoids.4 Therefore, a synthetic route leading to ortho-
Benzofurans, dihydrobenzofurans and their dimers in iso-
hydroxybenzofuran methyl ketones with particular
lated or rigid conformations are key structural units found
attributes would be of general interest.
in a large number of medicinal plants.2 They are usually
Numerous synthetic methodologies are available in the
active constituents of plant extracts used in traditional
literature for the construction of benzofuran ring and due
remedies, and play a pivotal role in the natural defence
to its wide-ranging applications; several new synthetic
mechanisms of their sources. A few structures representa-
approaches have been developed in recent years.5,6 The
most common procedures include palladium-catalyzed
coupling of substituted 2-halophenols and the appropriate
alkynes, a Dötz benzannulation approach using a,b-
tives of naturally occurring benzofurans3 are shown in
Figure 1. In nature’s library of benzofuran derivatives,
most features a benzofuran motif functionalized on
benzenoid ring with an adjacent hydroxy and acetyl
O
R2
HO
OH
H3C
O
HO
H3C
OAc
X
CH3
H3C
O
R
R1
O
O
CH3
O
O
O
euparone: R1 = OH, R2 = H, X = O
euparin: R1 = OH, R2 = H, X = CH2
isoeuparin: R1 = H, R2 = OH, X = CH2
ageratone: R = OAc
ageratone derivative: R = H
deacetylageratone: R = OH ageratone-based dimer: X = CH2
ageratone dimer: X = C(OH)CH2OAc
X
dehydrotremetone: R1 = R2 = H, X = CH2
O
O
H3C
CH3
O
R1
H
OR
RO
H3C
H
H
H3C
H3C
H
O
O
R2
O
O
O
tremetone: R1 = R2 = H
4-hydroxytremetone: R1 = OH, R2 = H
6-hydroxytremetone: R1 = H, R2 = OH
OH
dehydrotremetone-based dimer
viscidone: R = H
viscidone acetate: R = Ac
Figure 1 Examples of naturally occurring benzofurans, dihydrobenzofurans and their dimers bearing hydroxy and acetyl functionalities.
SYNLETT 2006, No. 10, pp 1497–1502
2
1
.0
6
.2
0
0
6
Advanced online publication: 12.06.2006
DOI: 10.1055/s-2006-944194; Art ID: G10206ST
© Georg Thieme Verlag Stuttgart · New York

1498
M. Dixit et al.
LETTER
unsaturated chromium carbene complexes and copper- isomeric benzofurans A–E together with the Amberlyst
catalyzed intramolecular ring-closure reactions. Unfortu- 15 catalyzed controlled dimerization of these benzofurans
nately the extension of these procedures in preparing nat- to bibenzofurans, which are similar to naturally occurring
urally occurring benzofurans suffers from the limited use bis(benzofurans) and apparently formed by a similar
of expensive palladium catalysts, the selective preparation mechanism.
of organometal complexes, the protection–deprotection of
Our strategy for the synthesis of 5-acetyl-4-hydroxy-
benzofuran (A) and 5-acetyl-6-hydroxybenzofuran (B)
include a reaction of resacetophenone (1) and bromo-
free hydroxy and acetyl functionality and/or harsh reac-
tion conditions. Recently, Kotschy et al.7 highlighted the
difficulties they encountered in the total synthesis of de-
acetaldehyde diethyl acetal in the presence of anhydrous
hydrotremetone in which Sonogashira coupling failed
potassium carbonate in dry DMF, which afforded 1-[4-
even under the best conditions known today. Though
(2,2-diethoxyethoxy)-2-hydroxyphenyl]ethanone (2) in
these natural products (Figure 1) are structurally very sim-
90% yield (Scheme 1). Many examples of the cyclization
ple but only the partial synthesis of some of the natural
of functionalized phenoxyacetals to corresponding benzo-
benzofurans (euparin, tremetone and dehydrotremetone)
furans are reported10 in the literature using various Lewis
using functionalized benzofurans as precursors have been
acids (SnCl4, AlCl3, BF3, ZnCl2) and organic acids
reported, and these have involved multiple steps.8 The
(H2SO4, TFA, H3PO4, PPA, HCOOH, PTSA). Unfortu-
wide-ranging applications and limitations of existing pro-
nately, the majority of them leads to low yield of desired
tocols prompted us to devise a general synthetic strategy
benzofuran along with major polymerized resinous mate-
directed towards the preparation of the core benzofurans
rial containing mixture of compounds. These cyclizations
are extremely dependent on the presence of substituents
with an adjacent hydroxy and acetyl functionality.
on the phenyl ring and the conditions employed. During
these investigations we found that this ring-closure step
OH
H3COC
HO
H3COC
can be effectively performed using Amberlyst 15 (A 15, a
sulfonic acid cation exchange resin) as a catalyst and
polymerization step can be controlled with concomitant
removal of azeotropes generated in situ during cycliza-
tion. Thus we attempted cyclization of phenoxyacetal 2 in
refluxing toluene using Amberlyst 15 as a catalyst with
concomitant removal of azeotropes using Dean–Stark
apparatus. Interestingly, two major products, 5-acetyl-4-
hydroxybenzofuran (3) and 5-acetyl-6-hydroxybenzo-
furan (4) were isolated in 38% and 54% yield, respective-
ly (Scheme 1). In the absence of Dean–Stark apparatus,
the cyclization of 2 resulted in extensive polymerization,
leading to a resinous substance containing a mixture of
compounds as a major product, similar to the polymeric
compound obtained by various acid-catalyzed cycliza-
tions (Scheme 1).
O
HO
O
COCH3
O
B
C
A
COCH3
HO
H3COC
HO
O
H3COC
O
O
OH
D
E
F
Figure 2 Six possible isomers of hydroxybenzofuran methyl ketone
(A–F).
There are only six isomeric structures possible in ortho-
hydroxybenzofuran methyl ketones (A–F) with the con-
sideration that only one hydroxy and one acetyl group is
attached adjacent to each other on the benzenoid ring of
the benzofuran as shown in Figure 2. Although these
benzofurans A–F are structurally very simple, they have
been prepared mainly through manipulation on properly
functionalized benzofurans in multiple steps in moderate
yields.9 In this paper we report two-step synthesis of
Such a minor change in the reaction conditions for the
cyclization of phenoxyacetals to benzofuran prompted us
to identify compounds from the resinous mixture, which
have not been reported prior to this study. On repeated
column chromatography in combination with preparative
OH
OH
OH
COCH3
COCH3
OH
COCH3
+
COCH3
BrCH2CH(OEt)2
A 15
DMF, 160 °C
O
O
(EtO)2HCH2CO
Dean–Stark
apparatus
HO
2
3
4
1
A 15
A 15
without
Dean–Stark
apparatus
A 15
H3COC
H3COC
HO
OH
OH
H3COC
H3COC
+
resinous substance
O
O
O
O
HO
6
5
Scheme 1
Synlett 2006, No. 10, 1497–1502 © Thieme Stuttgart · New York

LETTER
Synthesis of Nature-Mimicking Benzofurans
1499
TLC separation, we isolated two products 5 and 6 from and 4. The compound 6-hydroxy-7-acetylbenzofuran (9
the resinous mixture in low yields. The mass spectrum of or C) was prepared in 85% yield by the reaction of 2,6-di-
compound 6 showed molecular ion peak at m/z = 352, hydroxyacetophenone 7 and bromoacetaldehyde diethyl
which corresponds to two units of benzofuran 3 or 4. The acetal to form a phenoxyacetal 8, followed by Amberlyst
1H NMR spectroscopic analysis of 6 revealed two methyl 15 catalyzed cyclization under simultaneous removal of
singlets at d = 2.53 and 2.68 ppm and two hydroxy group water using Dean–Stark assembly (Scheme 2). Similarly,
singlets at d = 12.46 and 13.02 ppm, and four aromatic 6-acetyl-5-hydroxybenzofuran (12 or D) and 4-acetyl-5-
protons singlets at d = 6.43, 6.99, 7.58 and 7.91 ppm, hydroxybenzofuran (13 or E) were synthesized in good
which confirmed the possibility of a dimer of benzofuran yields from commercially available 2,5-dihydroxyaceto-
4. A multiplet at d = 4.75–4.80 ppm for two protons and a phenone (10) through a phenoxyacetal intermediate 11 as
multiplet at d = 4.92–4.96 ppm for one proton revealed shown in Scheme 2.
that one of the furan rings of the dimer is reduced under
acidic conditions. These dimers can be of two types such
i
ii
as 2¢,3¢-dihydro[2,3¢]bibenzofuran or 2¢,3¢-dihydro[3,2¢]-
bibenzofuran depending upon substituents on the benzo-
furan ring. A literature search on dimerization of benzofu-
ran revealed that a natural benzofuran kellinone has been
reported to form a dimer under acidic conditions.11 The
presence of a peak at d = 6.46 ppm for CH-3 in 1H NMR
spectrum of 6 and absence of a peak at around d = 7.56
ppm for CH-2 proton allowed us to propose a structure as
5,5¢-diacetyl-6,6¢-dihydroxy-2¢,3¢-dihydro[2,3¢]bibenzo-
furan. Finally, the structure of 6 was confirmed by a single
crystal X-ray analysis.12 The conformation of 6 along with
the atomic numbering scheme is shown in Figure 3. Sim-
ilarly, other isolated product 5 was assigned as 5,5¢-di-
acetyl-4,4¢-dihydroxy-2¢,3¢-dihydro-[2,3¢]bibenzofuran.
The formation of bibenzofuran from phenoxyacetal re-
vealed that as soon as the benzofuran is formed through
HO
OH
COCH3
O
COCH3
9
HO
HO
OCH2CH(OEt)2
COCH3
7
8
HO
HO
H3COC
i
H3COC
OCH2CH(OEt)2
OH
11
10
ii
HO
HO
H3COC
+
H3COC
O
O
12
13
Scheme 2 Reagents and conditions: i) BrCH2CH(OEt)2, DMF,
cyclization, it got converted into bibenzofuran by self- 140 °C; ii) A 15, toluene, reflux.
dimerization in aqueous acidic medium. These bibenzo-
furans are similar to natural dimers of ageratone or dehy-
drotremetone as shown in Figure 1.
Apart from naturally occurring benzofurans, natural
dimers have also been isolated from Ageratum housto-
nianum,3g Ophryosporus charua3h and Encelia
canescens3i in minor quantities. The biosynthetic route of
such dimers have been proposed through a Diels–Alder-
type reaction between two units of ageratone or
dehydrotremetone, followed by allylic hydroxylation or
hydroperoxidation of the initial adducts.3h An alternative
biosynthetic approach for natural dimeric chromenes and
mixed dimers has been proposed through acid-catalyzed
addition of 6-hydroxytremetone to acetyl chromene fol-
lowed by isomerization.3i The formation of similar type of
benzofuran dimers (5 and 6) from acid-catalyzed cycliza-
tion of phenoxyacetals supports the mechanism proposed
by Bohlmann et al.3i for the formation of mixed dimers.
Recently five-membered heteroaryl-based atropisomeric
ligands have been developed for asymmetric synthesis.13
Therefore, we became interested to prepare dimers of
these benzofurans (3, 4, 9, 12–14) in the presence of
Amberlyst 15 separately. The precursor 14 was prepared
by the reaction of diazocyclohexane-1,3-dione with vinyl
acetates in presence of rhodium acetate followed by dehy-
dration, esterification and aromatization.4h Compound 3
on refluxing in toluene with Amberlyst 15 selectively af-
forded 2¢,3¢-dihydro[2,3¢]bibenzofuran (5) in 89% yield
along with some unreacted benzofuran 3. Similarly an-
other set of compounds (4, 9, 12–14, Table 1) was treated
Figure 3 ORTEP view of compound 6 with arbitrary numbering.
With the demonstration of the utility of this route, we set
out to prepare a series of substituted benzofurans (C–F)
and their dimeric bibenzofurans in a controlled manner.
These benzofurans (C–F) with adjacent hydroxy and
acetyl groups have been prepared either from functional-
ized benzofurans9a,b or coumarins9c in multisteps. Our ap-
proach for preparing these useful benzofurans followed a
two-step procedure as demonstrated for the compounds 3
Synlett 2006, No. 10, 1497–1502 © Thieme Stuttgart · New York

1500
M. Dixit et al.
LETTER
Me
O
Table 1 Amberlyst 15 Catalyzed Dimerization of ortho-Hydroxy-
benzofuran Methyl Ketones
O
H
O
Reactant
Product
Yield
(%)
4
SO3H
OH
H3COC
HO
COCH3
OH
Me
O
Me
O
Me
O
H3COC
89
81
+
O
O
O
H
O
H
O
H
O
3
4
O
O
O
O
+
+
5
H
C
A
B
H3COC
COCH3
OH
OH
4
H3COC
H
H3COC
HO
H3COC
OH
OH
Me
O
O
O
H+
H3COC
HO
O
6
H
O
O
+
O
O
OH
COCH3
6
D
O
OH
COCH3
92
75
Scheme 3 A possible mechanism for dimerization of 5-acetyl-6-hy-
droxybenzofuran.
O
O
HO
9
COCH3
15
furan derivatives bearing hydroxy and acetyl groups at
adjacent positions, which were difficult to prepare
through known methodologies. We have also demonstrat-
ed an Amberlyst 15 catalyzed, controlled dimerization of
these benzofurans to 2¢,3¢-dihydro[2,3¢]bibenzofurans,
which are similar to the natural dimers. In particular, the
synthesis of ortho-hydroxybenzofuran methyl ketone
requires concomitant removal of an azeotropic mixture
during the cyclization of phenoxyacetals; however, bi-
benzofurans can directly be prepared without removal of
azeotropic contents. The ease of controlled cyclization
and selective dimerization in the presence of the catalyst
Amberlyst 15 and its reusability over several uses opens a
new avenue in the exploration of the chemical and bio-
logical potential of these interesting molecules.
OH
HO
COCH3
O
COCH3
HO
H3COC
12
O
O
16
COCH3
HO
OH
H3COC
H3COC
HO
83
86
O
13
O
O
17
OH
H3COOC
HO
COOCH3
OH
H3COOC
O
14
O
O
Acknowledgment
18
Authors are grateful to SAIF, CDRI, Lucknow for providing
spectroscopic data of the synthesized compounds. The financial
assistance by Department of Science and Technology (DST) and
Council of Scientific and Industrial Research (CSIR), New Delhi is
gratefully acknowledged.
under the same reaction conditions to afford bibenzo-
furans (6, 15–18) in good yields. All the synthesized com-
pounds were characterized by spectroscopic analyses.14,15
With these observations, we propose a possible mecha-
nism for the formation of bibenzofuran from ortho-
hydroxybenzofuran methyl ketone in the presence of
Amberlyst 15 catalyst (Scheme 3). The mechanism for the
dimerization, using Amberlyst 15 might involve protona-
tion of benzofuran 4 to form a carbonium ion intermediate
C followed by attack of the other molecule of 4 at the b-
position of the intermediate C to form an intermediate
bibenzofuran D. This intermediate on deprotonation
affords 2¢,3¢-dihydro-[2,3¢]bibenzofuran (6) as shown in
Scheme 3.
References and Notes
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In summary, we have demonstrated a highly convenient
two-step general synthesis of nature-mimicking benzo-
Synlett 2006, No. 10, 1497–1502 © Thieme Stuttgart · New York

LETTER
Synthesis of Nature-Mimicking Benzofurans
1501
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The phenoxyacetal (2, 8, 11; 20 g, 0.075 mol) was refluxed
in dry toluene (30 mL) with Amberlyst 15 (2.5 g) at 120 °C
for 6–8 h with concomitant removal of the azeotrope using a
Dean–Stark apparatus. The resulting reaction mixture was
filtered and the resin was washed with an excess of toluene.
The filtrate thus obtained was concentrated to dryness and
two pure compounds were isolated by silica gel column
chromatography using EtOAc–hexane (1:10) as eluent.
Compound 3: white solid; mp 92–93 °C (Lit.4h 92–93 °C).
MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1640 (CO), 3421
(OH) cm–1. 1H NMR (200 MHz, CDCl3): d = 2.66 (s, 3 H,
CH3), 7.00 (d, J = 2.2 Hz, 1 H, H-3), 7.04 (d, 1 H, J = 8.8 Hz,
H-7), 7.57 (d, 1 H, J = 2.2 Hz, H-2), 7.66 (d, 1 H, J = 8.8 Hz,
H-6), 13.28 (s, 1 H, OH).
Compound 4: white solid; mp 101–102 °C (Lit.9a 96 °C).
MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1638 (CO), 3426
(OH) cm–1. 1H NMR (200 MHz, CDCl3): d = 2.70 (s, 3 H,
CH3), 6.72 (d, 1 H, J = 2.2 Hz, H-3), 7.04 (s, 1 H, H-7), 7.56
(d, 1 H, J = 2.2 Hz, H-2), 8.00 (s, 1 H, H-4), 12.40 (s, 1 H,
OH).
Compound 9: white solid; mp 111–112 °C (Lit.9c 110 °C).
MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1638 (CO), 3432
(OH) cm–1. 1H NMR (200 MHz, CDCl3): d = 2.90 (s, 3 H,
CH3), 6.76 (d, J = 2.2 Hz, 1 H, H-3), 6.90 (d, 1 H, J = 8.6 Hz,
H-5), 7.62 (d, 1 H, J = 2.2 Hz, H-2), 7.66 (d, 1 H, J = 8.6 Hz,
H-4), 12.85 (s, 1 H, OH).
Compound 12: white solid; mp 120–121 °C. MS (FAB):
m/z = 177 [M+ + 1]. IR (KBr): 1629 (CO), 3447 (OH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.60 (s, 3 H, CH3), 6.86 (s,
1 H, ArH), 6.91 (d, J = 2.2 Hz, 1 H, H-3), 7.02 (s, 1 H, ArH),
7.19 (d, 1 H, J = 2.2 Hz, H-2), 11.81 (s, 1 H, OH).
Compound 13: white solid; mp 98–99 °C (Lit.9a 103–
104 °C). MS (FAB): m/z = 177 [M+ + 1]. IR (KBr): 1628
(CO), 3443 (OH) cm–1. 1H NMR (200 MHz, CDCl3):
d = 2.80 (s, 3 H, CH3), 6.94 (d, 1 H, J = 9.0 Hz, CH), 6.98 (d,
1 H, J = 2.2 Hz, H-3), 7.64 (d, 1 H, J = 9.0 Hz, ArH), 7.76
(d, 1 H, J = 2.2 Hz, H-2), 13.02 (s, 1 H, OH).
(7) Csekei, M.; Novak, Z.; Timari, G.; Kotschy, A. ARKIVOC
2004, (vii), 285.
(8) (a) Ramachandran, P. K.; Cheng, T.; Horton, W. J. J. Org.
Chem. 1963, 28, 2744. (b) De Graw, J. I. Jr.; Bowen, D. M.;
Bonner, W. A. Tetrahedron 1963, 19, 19. (c) Alertsen, A.
R.; Anthonsen, T.; Raknes, E.; Sorensen, N. A. Acta Chem.
Scand. 1971, 25, 1919.
(9) (a) Ramachandran, P. K.; Tefteller, A. T.; Paulson, G. O.;
Cheng, T.; Lin, C. T. J. Org. Chem. 1963, 28, 398.
(b) Clavel, J.-M.; Guillaumel, J.; Demerseman, P.; Royer, R.
Compound 14: white solid; mp 104–105 °C (Lit.4h 105 °C).
MS (FAB): m/z = 193 [M+ + 1]. IR (KBr): 1678 (CO), 3502
Synlett 2006, No. 10, 1497–1502 © Thieme Stuttgart · New York

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M. Dixit et al.
LETTER
(OH) cm–1. 1H NMR (200 MHz, CDCl3): d = 3.97 (s, 3 H,
OCH3), 6.98 (d, J = 2.2 Hz, 1 H, H-3), 7.03 (d, 1 H, J = 8.8
Hz, H-7), 7.57 (d, 1 H, J = 2.2 Hz, H-2), 7.78 (d, 1 H, J = 8.8
Hz, H-6), 13.18 (s, 1 H, OH).
1H NMR (200 MHz CDCl3): d = 2.69 (s, 3 H, CH3), 2.82 (s,
3 H, CH3), 4.80–4.88 (m, 2 H, CH2), 4.97–5.02 (m, 1 H, CH),
6.44 (s, 1 H, CH), 6.52 (d, 1 H, J = 8.4 Hz, ArH), 6.88 (d, 1
H, J = 8.6 Hz, ArH), 7.30 (d, 1 H, J = 8.4 Hz, ArH), 7.56 (d,
1 H, J = 8.6 Hz, ArH), 12.74 (s, 1 H, OH), 12.81 (s, 1 H,
OH). 13C NMR (200 MHz CDCl3): d = 31.6 (CH3), 32.0
(CH3), 41.1 (CH), 77.2 (CH2), 103.5 (=CH), 107.3, 107.5,
110.3, 114.5, 117.2, 120.5, 128.5, 131.9, 154.2, 156.5,
161.8, 161.9, 164.0, 202.3, 203.5.
Compound 16: yellow solid; mp 192–193 °C. MS (FAB):
m/z = 353 [M+ + 1]. IR (KBr): 1648 (CO), 3422 (OH) cm–1.
1H NMR (200 MHz CDCl3): d = 2.53 (s, 3 H, CH3), 2.68 (s,
3 H, CH3), 4.75–4.80 (m, 2 H, CH2), 4.82–4.99 (m, 1 H, CH),
6.43 (s, 1 H, ArH), 6.46 (s, 1 H, CH), 6.99 (s, 1 H, ArH), 7.58
(s, 1 H, ArH), 7.91 (s, 1 H, ArH), 12.47 (s, 1 H, OH), 13.03
(s, 1 H, OH).
Compound 17: yellow semi-solid. MS (FAB): m/z = 353
[M+ + 1]. IR (KBr): 1645 (CO), 3437 (OH) cm–1. 1H NMR
(200 MHz CDCl3): d = 2.50 (s, 3 H, CH3), 2.57 (s, 3 H, CH3),
4.73–4.88 (m, 3 H, CH and CH2), 6.41 (d, 1 H, J = 8.6 Hz,
ArH), 6.61 (s, 1 H, CH), 6.95 (d, 1 H, J = 8.6 Hz, ArH),
7.50–7.66 (m, 2 H, ArH), 12.76 (s, 1 H, OH), 13.08 (s, 1 H,
OH).
Compound 18: yellow solid; mp 184–185 °C. MS (FAB):
m/z = 385 [M+ + 1]. IR (KBr): 1678 (CO), 3426 (OH) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.91 (s, 3 H, OCH3), 3.95
(s, 3 H, OCH3), 4.78–4.95 (m, 3 H, CH and CH2), 6.65 (s, 1
H, CH), 6.47 (d, 1 H, J = 8.6 Hz, ArH), 6.96 (d, 1 H, J = 8.8
Hz, ArH), 7.72 (d, 1 H, J = 8.8 Hz, ArH), 7.81 (d, 1 H,
J = 8.6 Hz, ArH), 12.42 (s, 1 H, OH), 13.01 (s, 1 H, OH).
(15) Synthesis of 2¢,3¢-Dihydro[2,3¢]bibenzofurans (5, 6 and
15–18) – General Procedure.
The ortho-hydroxybenzofuran methyl ketone (10 mmol)
was refluxed in toluene (35 mL) with Amberlyst 15 (0.22 g)
at 120 °C for 6–10 h. The resulting reaction mixture was
filtered and the resin was washed with an excess of toluene.
The filtrate thus obtained was concentrated to dryness and a
pure compound was isolated by silica gel column
chromatography using 7% EtOAc in hexane (1:10) as eluent.
Compound 5: yellow solid; mp 149–150 °C. MS (FAB):
m/z = 353 [M+ + 1]. IR (KBr): 1638 (CO), 3433 (OH) cm–1.
1H NMR (200 MHz CDCl3): d = 2.57 (s, 3 H, CH3), 2.64 (s,
3 H, CH3), 4.81–4.88 (m, 1 H, CH), 4.89–4.94 (m, 2 H, CH2),
6.48 (d, 1 H, J = 8.6 Hz, ArH), 6.68 (s, 1 H, CH), 6.96 (d, 1
H, J = 8.8 Hz, ArH), 7.60 (d, 1 H, J = 8.8 Hz, ArH), 7.70 (d,
1 H, J = 8.6 Hz, ArH), 12.83 (s, 1 H, OH), 13.15 (s, 1 H,
OH).
Compound 6: yellow solid; mp 189–190 °C. MS (FAB):
m/z = 353 [M+ + 1]. IR (KBr): 1641 (CO), 3427 (OH) cm–1.
1H NMR (200 MHz CDCl3): d = 2.53 (s, 3 H, CH3), 2.68 (s,
3 H, CH3), 4.75–4.80 (m, 2 H, CH2), 4.92–4.96 (m, 1 H, CH),
6.43 (s, 1 H, ArH), 6.46 (s, 1 H, CH), 6.99 (s, 1 H, ArH), 7.58
(s, 1 H, ArH), 7.91 (s, 1 H, ArH), 12.46 (s, 1 H, OH), 13.02
(s, 1 H, OH).
Compound 15: yellow solid; mp 110–111 °C. MS (FAB):
m/z = 353 [M+ + 1]. IR (KBr): 1637 (CO), 3449 (OH) cm–1.
Synlett 2006, No. 10, 1497–1502 © Thieme Stuttgart · New York