Halogen-metal exchange/cyclization of iodoketones: A direct synthesis of 3-arylbenzofurans

Article abstract of DOI:10.1055/s-2005-872690

The first synthesis of benzofuran 2 was achieved in 17% overall yield in seven steps. The key step was a halogen-metal exchange/cyclization reaction. Several examples of this reaction were reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-872690

2504
LETTER
Halogen–Metal Exchange/Cyclization of Iodoketones: A Direct Synthesis
of 3-Arylbenzofurans
D
irec
t
Synthesis
o
e
f
3-Arylben
o
zofurans rge A. Kraus*,* Jacob D. Schroeder
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Fax +1(515)2940105; E-mail: gakraus@iastate.edu
Received 20 July 2005
OMe
OMe
MeO
CHO
Abstract: The first synthesis of benzofuran 2 was achieved in 17%
MeO
OMe
I
overall yield in seven steps. The key step was a halogen–metal ex-
change/cyclization reaction. Several examples of this reaction were
reported.
1. MeLi
–78 °C
OMe
O
2. PTSA
75%
O
OMe
OMe
Key words: benzofuran, halogen–metal exchange/cyclization reac-
tion, arylbenzofuran
O
3
4
Scheme 1
Benzofurans are common subunits in many biologically
active natural and synthetic products.1 In particular, ben-
zofurans bearing a 3-aryl substituent exhibit useful anti-
cancer,2 antiviral,3 and immunomodulatory4 effects. Two
examples are isoparvifuran (1),5 an antifungal agent, and
2,6 a promising antiandrogenic agent (Figure 1). Benzo-
furans have been produced by a variety of methods7 in-
cluding cyclodehydration of aryl ketones,8 palladium-
mediated Heck reactions,9 radical reactions,10 and Wittig
and McMurry reactions.11
these conditions were applied to the corresponding bro-
moketones, addition to the carbonyl group produced only
tertiary alcohols in good yields.
As can be seen from Table 1, yields of both the phenol
alkylation and halogen–metal exchange/cyclization steps
are very good. Iodoketone 5 was synthesized to determine
whether aliphatic ketones would yield benzofurans. Reac-
tion of 5 with methyllithium at –78 °C afforded 6 in 88%
yield (Scheme 2).
OMe
OMe
Me
I
O
MeLi
O
HO
HO
Me
O
O
O
Me
MeO
MeO
O
6
5
1
2
Scheme 2
Ph
Figure 1
The synthesis of 2 began from phenol 9.15 Alkylation with
phenacyl bromide followed by iodination with N-iodo-
succinimide (NIS) and trifluoroacetic acid16 provided an
iodoketone which cyclized upon treatment with methyl-
lithium to produce benzofuran 10. The benzyl protecting
group was efficiently removed using in situ generated
iodotrimethylsilane to generate 11 in 72% yield
(Scheme 3). The other component needed for the
synthesis of 2 was aldehyde 12 which was synthesized
in 86% yield from readily available 2-hydroxy-4,5-
dimethoxybenzaldehyde17 by reaction with cinnamyl
bromide and potassium carbonate.
As part of an approach to malibatol A,12 we discovered
that iodoketone 3 reacted with methyllithium to generate
benzofuran 4 (Scheme 1). This was the first reported for-
mation of a benzofuran by an intramolecular cyclization
initiated by halogen–metal exchange. Kihara had previ-
ously reported that iodoamides reacted with alkyllithiums
to form indoles.13 We describe herein several examples of
this novel cyclization protocol, including an example us-
ing an aliphatic ketone.
The synthesis of a number of 3-arylbenzofurans is illus-
trated below in Table 1. The sequence begins with the
alkylation of an iodophenol with an a-bromoketone and
potassium carbonate. The resulting iodoketone is treated
with methyllithium in THF at –78 °C.14 Aqueous work up
followed by acid treatment yielded the benzofuran. When
1. PhCOCH2Br,
K2CO3
BnO
MeO
RO
H
2. NIS, CF3CO2H
3. MeLi
OH
O
MeO
9
10: R = Bn
11: R = H
TMSI
SYNLETT 2005, No. 16, pp 2504–2506
0
4
.1
0
.2
0
0
5
Advanced online publication: 21.09.2005
DOI: 10.1055/s-2005-872690; Art ID: S06705ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3

LETTER
Direct Synthesis of 3-Arylbenzofurans
2505
Table 1 Benzofuran Formation
Ar
R2
O
I
I
Br
K2CO3
MeLi
R2
Ar
+
Ar
R1
O
O
R2
R1
OH
O
R1
8
7
Entry
R1
R2
Ar
Yield of 7 (%)
Yield of 8 (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
Phenyl
97
99
78
84
97
80
81
97
77
79
8a
8b
8c
8d
8e
8f
H
2¢-MeOPh
4¢-MeOPh
2¢,4¢,5¢-MeOPh
Phenyl
H
80
H
72
OMe
H
H
100
100
83
Me
H
Phenyl
H
Thiophen-2-yl
Furan-2-yl
8g
8h
H
H
75
Formation of the dianion of 11 using two equivalents of n- able and the reaction is operationally convenient. The syn-
butyllithium in THF at –78 °C followed by addition of 12 thesis of 2 was achieved in 7 steps in 17% overall yield
(Figure 2) produced compound 13 in 57% yield. Unfortu- from 9.
nately, repeated attempts to deoxygenate18 13 (Et3SiH,
TFA; Et3SiH, BF3·OEt2; Na, NH3; NaBH4, TFA) led to
decomposition. Interestingly, storage of 13 in chloroform
Acknowledgment
We thank the National Institutes of Health (grant P01 ES12020) and
the Office of Dietary Supplements for financial support through the
Center for Research on Botanical Dietary Supplements at Iowa
State University. We thank Professor Shirota for providing NMR
spectra of 2.
containing deuteriochloroform from NMR experiments
led to the formation of ether 14. The yield of 14 was im-
proved by the use of ethanol as a co-solvent. Remarkably,
reduction of ether 14 using triethylsilane and trifluoroace-
tic acid (TFA) afforded 2 in 73% yield (Scheme 4). Com-
parison of our 1H NMR and 13C NMR spectra with those
provided by Professor Shirota confirmed our synthesis of
2.
References
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OMe
OMe
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12
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Ph
Figure 2
OMe
OMe
HO
2 n-BuLi
11
O
MeO
12
X
O
13: X = OH
14: X = OEt
2
EtOH, CDCl3
Et3SiH, TFA
Ph
Scheme 4
Synlett 2005, No. 16, 2504–2506 © Thieme Stuttgart · New York

2506
G. A. Kraus, J. D. Schroeder
LETTER
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(s, 1 H), 6.68 (s, 1 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.83 (s, 3
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Five equiv of MeLi (1.6 M solution in Et2O) were added via
syringe to 4 mL of THF at –78 °C. To this solution was
added 1 equiv of the iodoketone (in 4 mL of THF) dropwise
via syringe. After addition, the reaction was allowed to stir
at –78 °C for 15 min. The reaction was allowed to slowly
warm to r.t., and was quenched by the addition of 4 mL of aq
NH4Cl solution. After 5 min, the reaction was extracted into
EtOAc, washed with brine (2 × 10 mL), dried over MgSO4,
filtered, and concentrated. The crude product was then
dissolved in 10 mL of acetone, and 5 mL of a 10% aq PTSA
Synlett 2005, No. 16, 2504–2506 © Thieme Stuttgart · New York