Controlled synthesis of 2-and 3-substituted benzo[ b ]furans

Article abstract of DOI:10.1021/ol102123u

A controlled regioselective synthesis of either C-2 or C-3 substituted benzo[b]furans from readily accessible 1-(2-hydroxyphenyl)-2-chloroethanones is described. Addition of a range of Grignard reagents to the α-chloro ketones generates alkoxide intermediates, which can form either 2-substituted benzo[b]furans via a [1,2]-aryl migration or 3-substituted benzo[b]furans via a direct cyclization and dehydration sequence. A temperature-dependent [1,2]-aryl migration mechanism for the formation of 2-substituted benzo[b]furan is proposed.

Full text of DOI:10.1021/ol102123u

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4972-4975
Controlled Synthesis of 2- and
3-Substituted Benzo[b]furans
Tao Pei,* Cheng-yi Chen, Lisa DiMichele, and Ian W. Davies
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065, United States
tao_pei@merck.com
Received September 6, 2010
ABSTRACT
A controlled regioselective synthesis of either C-2 or C-3 substituted benzo[b]furans from readily accessible 1-(2-hydroxyphenyl)-2-chloroethanones
is described. Addition of a range of Grignard reagents to the r-chloro ketones generates alkoxide intermediates, which can form either
2-substituted benzo[b]furans via a [1,2]-aryl migration or 3-substituted benzo[b]furans via a direct cyclization and dehydration sequence. A
temperature-dependent [1,2]-aryl migration mechanism for the formation of 2-substituted benzo[b]furan is proposed.
Benzofurans, as a core structural motif, are ubiquitous in
natural products as well as pharmaceutical compounds, such
as Amiodarone and (-)-BPAP.1 The pursuit of a general
and efficient synthesis of benzo[b]furans that controls the
introduction of substituents in a regioselective fashion has
been of continued interest to synthetic organic chemists.
Many existing approaches focus on the formation of the furan
ring from a variety of substrates while introducing substit-
uents at C-2 and C-3.2 The synthesis of either 2- or
3-substituted benzo[b]furans from the same substrate, how-
ever, remains elusive and would have great advantages over
existing protocols. Herein, we wish to report a controlled
and regioselective synthesis of either C-2 or C-3 substituted
benzo[b]furans from readily accessible 1-(2-hydroxyphenyl)-
2-chloroethanones.3
We recently reported an efficient synthesis of 2-substituted
indoles (2) from readily accessible 1-(2-aminophenyl)-2-chlo-
roethanones (1) and commercially available organometallic
reagents (Scheme 1).4 The highly regioselective introduction
of substituents at C-2 was achieved via a novel [1,2]-aryl
migration mechanism. We subsequently observed that a similar
migration was feasible when 1-(2-hydroxyphenyl)-2-chloroet-
hanone (3) was treated with excess Grignard.5 The [1,2]-aryl
migration for this reaction happened at a slower rate compared
to its nitrogen counterpart in the synthesis of indoles, thus
requiring elevated temperature to facilitate the migration. The
key intermediate phenoxy ketone 5 was formed cleanly and
cyclized under acidic conditions to successfully generate
(1) (a) Donelly, D. M. X.; Meegan, M. J. Furans and Their Benzo
Derivatives: (iii) Synthesis and Applications. In ComprehensiVe Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Pergamon: New York, 1984; Vol. 4, pp
657-712. (b) Luca, L. D.; Nieddu, G.; Porcheddu, A.; Giacomelli, G. Curr.
Med. Chem. 2009, 16, 1. (c) Banskota, A. H.; Tezuka, Y.; Midorikawa, K.;
Matsushige, K.; Kadota, S. J. Nat. Prod. 2000, 63, 1277. (d) Punnam, S. R.;
Goyal, S. K.; Kotaru, V. P. K.; Pachika, A. R.; Abela, G. S.; Thakur, R. K.
CardioVasc. Hematol. Disord: Drug Targets 2010, 10, 73. (e) Dawson,
L. A.; Watson, J. M. CNS Neurosci. Ther. 2009, 15, 107. (f) Ohtsuka, T.;
Aoka, Y. Drugs Future 2003, 28, 143.
(3) These compounds can be prepared via Friedel-Crafts acylation from
corresponding phenols and nitriles. See: (a) Sugasawa, T.; Toyoda, T.;
Adachi, M.; Sasakura, K. J. Am. Chem. Soc. 1978, 100, 4842. (b) Sugasawa,
T.; Adachi, M.; Sasakura, K.; Kitagawa, A. J. Org. Chem. 1979, 44, 578.
(4) (a) Pei, T.; Chen, C.; Dormer, P. G.; Davies, I. W. Angew. Chem.,
Int. Ed. 2008, 47, 4231. (b) Pei, T.; Tellers, D.; Streckfuss, E.; Chen, C.;
Davies, I. W. Tetrahedron 2009, 65, 3285.
(2) For recent reviews of the synthesis of benzofurans, see: Hou, X.-L.;
Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog. Heterocycl. Chem. 2009,
21, 179.
(5) Similar [1,2]-aryl migration was observed when 1-(4-hydroxyphenyl)-
2-chloroethanone was treated with excess methyl Grignard. See: Crombie,
L.; Hardy, R.; Knight, D. W. J. Chem. Soc., Perkin Trans. 1 1985, 1373.
10.1021/ol102123u  2010 American Chemical Society
Published on Web 09/28/2010

Scheme 1
.
Synthesis of 2-Substituted Indoles from 1 via
Scheme 3
.
Synthesis of 2-Substituted Benzo[b]furans 6 from
Ketone 3 under Condition Aa b
,
[1,2]-Aryl Migration
2-substituted benzo[b]furans in moderate to good yields.
Furthermore, we found that the migration process could be
halted by quenching the reaction at low temperature to give
the alcohol intermediate 7. Subsequent cyclization-elimination
of the alcohol intermediate 7 then allowed access to isomeric
3-substituted benzo[b]furans (Scheme 2). On the basis of these
a Condition A: A solution of ketone 3 (1.0 mmol) in 2.0 mL of THF/
toluene (1:1 v/v) was mixed with the Grignard reagent (3.0 mmol) at -10
°C. The cold bath was removed, and the mixture was stirred at room
temperature for 30 min and then at 55 °C for 1 h, cooled to room
temperature, quenched with 1.2 mL of 5 M HCl/IPA, and heated at 70 °C
for 10 min. b All reactions were carried out without optimization. Yields
refer to isolated material based on ketone 3.
Scheme 2
.
Proposed Mechanism for the Synthesis of 2- and
3-Substituted Benzo[b]furans from 3
Having successfully prepared a range of 2-substituted ben-
zo[b]furans 6 from ketone 3 employing various RMgX reagents,
we decided to extend this methodology to substituted ketones
10. Under condition A, a series of 2-substituted benzo[b]furans
11 were readily synthesized in moderate to good yields (Scheme
4). It was found that neither electron-donating nor electron-
Scheme 4
.
Synthesis of 2-Substituted Benzo[b]furans 11 from
Ketone 10 under Condition Aa b
,
promising initial results, we believed that the reaction of 1-(2-
hydroxyphenyl)-2-chloroethanones with various Grignard re-
agents could be developed into a versatile method for direct
access to 2- and 3-substituted benzo[b]furans.
We first explored the generality of the controlled synthesis
of 2-substituted benzo[b]furans by adding different Grignard
reagents to 1-(2-hydroxyphenyl)-2-chloroethanone (3), and the
results are summarized in Scheme 3. Reaction of 3 with
nBuMgCl at 55 °C for 1 h followed by treatment with HCl/
IPA at 70 °C for 10 min formed 2-butylbenzo[b]furan (6a) in
66% isolated yield (condition A). Similar to nBuMgCl, other
primary alkyl Grignard reagents reacted with 3 to form
2-substituted benzo[b]furans in good yields. For example,
2-ethylbenzo[b]furan (6b), a key intermediate in the synthesis
of Benziodarone,6 a vasodilator, was easily prepared in 68%
isolated yield from 3 and EtMgCl under condition A. Under
the same conditions, bulky Grignard 2,2-dimethyl-2-phenylethyl
magnesium bromide led to formation of 2-substituted benzo[b]-
furan 6d in 76% yield. Introduction of aromatic substituents,
such as a phenyl (6e) or thien-2-yl (6f) group, to C-2 of
benzo[b]furan using corresponding aromatic Grignard reagents
also worked well. When the secondary Grignard cyclohexyl
magnesium bromide was used, 2-cyclohexylbenzo[b]furan (6g)
was obtained in only 38% isolated yield.
a Reaction conditions: ketone 10 (1.0 mmol) in 2.0 mL of THF/toluene
(1:1 v/v) and Grignard (3.0 mmol) were reacted under condition A. b All
reactions were carried out without optimization. Yields refer to isolated
material based on ketone 10.
withdrawing substituents on the aromatic ring had much impact
on the transformation. For instance, 2-benzyl-5-methoxyben-
zo[b]furan (11a) and 6-t-butyl-(2,2-dimethyl-2-phenyl)ethyl-
benzo[b]furan (11e), with electron-donating groups on the
phenyl ring, were prepared in 58% and 59% yield, respectively.
In addition, ketones with electron-withdrawing Cl and Br
substituents on the phenyl ring also reacted with Grignard
reagents in good yields. Under the identical conditions, 2,3-
(6) Buu Hoi, N. P.; Beaudet, C. US Patent, 1961, 3041042.
Org. Lett., Vol. 12, No. 21, 2010
4973

disubstituted benzo[b]furan 11b was prepared in 72% isolated
yield from ketone 10b (R1 ) Me, X ) H) and nBuMgCl.
In contrast to the facile [1,2]-aryl migration in the reaction
of 1-(2-aminophenyl)-2-chloroethanones (1) with Grignard
Table 1. Impact of Base and Counter Ion on the Direct
Cyclization vs [1,2]-Aryl Migration of Alcohol 7aa
4
ꢀ
at below -40 C, the reaction of 1-(2-hydroxyphenyl)-2-
chloroethanone (3) with Grignard nBuMgCl needed 12 h at
ꢀ
ambient temperature or 1 h at 50 C to complete the [1,2]-
aryl migration. 2-Butylbenzo[b]furan (6a) was isolated in
66% yield exclusively after heating the alkoxide intermediate
for 1 h at 55 °C followed by HCl-mediated benzofuran ring
formation (Scheme 3). There was no migration observed
entry
base
solvent
6ab
12ab
1c
2c
nBuMgCl, 2.0 M
nBuLi, 2.5 M
nBuLi, 2.5 M
NaOH, 5.0 M in water
pyridine
THF
THF
THF
MeOH
THF
THF
THF
THF
100
52
22
32
0
9
7
2
0
48
78
68
0
91
93
98
ꢀ
below -30 C, and in fact, alcohol 7a could be isolated in
3c e
,
81% yield after the reaction was quenched with MeOH at
4d
5d
6d
ꢀ
-30 C. Treatment of 7a with 2.5 equiv of Grignard at 55
°C facilitated [1,2]-aryl migration to form 2-butylbenzo[b]-
furan (6a) in 77% isolated yield as a single regioisomer after
subsequent cyclization and dehydration (Scheme 5).
Et3N
7d f
K2CO3, saturated in water
K2CO3, 2.0 M in water
,
8d f
,
a Alchol 7a (0.50 mmol) and base were mixed in 1.0 mL of solvent at
room temperature for 12 h, and HCl/IPA was added (5 M, 1.0 mL) and
heated at 70 °C for 10 min. b Regioisomeric ratio determined by HPLC.
c Base, 2.0 mmol. d Base, 5.0 mmol. e Reaction was run at 55 ꢀC for 1 h
before addition of HCl. f Reaction was run with nBu4NHSO4 (0.1 mmol).
Scheme 5
.
Synthesis of Benzofuran 6a and 12a from 3 via
Alcohol 7a
With the optimized conditions identified, several 3-sub-
stituted benzo[b]furans were successfully synthesized em-
ploying the three-step sequence.7 Hence, treatment of ketones
ꢀ
10 with a variety of Grignard reagents at below -30 C
generated the crude alcohol intermediates, which cyclized
upon treatment with 2 M aqueous K2CO3 and nBu4NHSO4.
Finally, dehydration of the cyclized intermediate using 5 M
HCl/IPA led to 3-substituted benzo[b]furans 12 (condition
B). As shown in Scheme 6, 3-butylbenzo[b]furan (12a),
The sluggishness of the [1,2]-aryl migration of alkoxide
4 at low temperature prompted us to explore another reaction
pathway toward the synthesis of 3-substituted benzo[b]furan
via a ring-closure-elimination sequence, namely, direct
cyclization of alcohol and subsequent dehydration (Scheme
2). While the use of nBuMgCl as base led to exclusive [1,2]-
aryl migration and the formation of 2-butylbenzo[b]furan
(6a), use of nBuLi led to formation of a mixture of 2- and
3-butylbenzo[b]furans (6a and 12a) at both ambient tem-
Scheme 6. Synthesis of 3-Substituted Benzo[b]furans from 10a b
,
ꢀ
perature and 55 C (Table 1). It appeared that the weakly
nucleophilic magnesium alkoxide in 4 disfavored the direct
cyclization of 4 to 12a when compared to the [1,2]-aryl
migration leading to 6a. Similarly, when alcohol 7a was
mixed with 5 M aqueous NaOH solution at room temperature
in MeOH, followed by addition of HCl in IPA, a mixture of
6a and 12a was obtained. A quick screen of bases showed
that a mild aqueous base was key to the direct cyclization
of alchol 7a with little competition from the [1,2]-aryl
migration. While no reaction occurred when pyridine was
used in THF, a slow but selective direct cyclization to 12a
was observed with triethylamine in THF. Use of a saturated
aqueous K2CO3 solution led to increased cyclization and
decreased [1,2]-aryl migration. Finally, 2 M aqueous K2CO3
with nBu4NHSO4 was identified as the optimum conditions
to achieve clean cyclization with little [1,2]-aryl migration.
After dehydration under acidic conditions, 3-butylbenzo[b]-
furan (12a) was isolated in 80% yield from 7a (Scheme 5).
a Condition B: A solution of ketone 10 (1.0 mmol) in 2.0 mL of THF/
toluene (1:1 v/v) was mixed with the Grignard reagent (2.5 mmol) at -78
°C, slowly warmed to -30 °C over 30 min, quenched with cold MeOH,
and warmed to room temperature, and 2 M aqueous HCl was added. The
separated organic layer was stirred with 2.0 mL of 2 M aqueous K2CO3
and 0.10 mmol nBu4NHSO4 for 12 h; the aqueous layer was removed; and
1.0 mL of 5 M HCl/IPA was added and heated at 70 °C for 10 min. b All
reactions were carried out without optimization. Yields refer to isolated
material based on ketone 10.
4974
Org. Lett., Vol. 12, No. 21, 2010

3-benzylbenzo[b]furan (12b), and 3-phenylbenzo[b]furan
(12c) were isolated in 60%, 77%, and 65% yield, respec-
tively. In addition, ketones with methoxy substitution on the
phenyl ring also reacted to form the 3-substituted benzo[b]-
furan 12d and 12e in good yields.
In summary, we have discovered and developed a versatile
method for the regioselective synthesis of either 2- or
3-substituted benzo[b]furans from a single chloroketone
starting material. The reaction proceeds via a unique [1,2]-
aryl rearrangement followed by intramolecular condensation
to form the 2-substituted benzo[b]furan under condition A.
Under condition B, the reaction goes through the same
alkoxide intermediate but directly cyclizes and dehydrates
to form the corresponding 3-substituted benzo[b]furan. The
method allows easy control of the introduction of substituents
at the C-2 or C-3 position of the benzo[b]furan and tolerates
various substitution patterns in the substrates. It provides
rapid access to a variety of structurally useful benzo[b]furans
and hence could serve as a versatile tool for the modular
synthesis of benzo[b]furan-containing medicinal agents.
Acknowledgment. The authors would like to thank
Professor Eric Jacobsen (Harvard University) for helpful
discussions.
Supporting Information Available: Experimental pro-
cedure, spectroscopic and analytical data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(7) 3-Substituted benzofurans can also be prepared from compound 3
via formation of 2,3-dihydro-1-benzofuran-3-one. For reaction of 2,3-
dihydro-1-benzofuran-3-one with Grignard reagents, see: Stoermer, B. Chem.
Ber. 1915, 48, 68.
OL102123U
Org. Lett., Vol. 12, No. 21, 2010
4975