Metal-free one-pot synthesis of benzofurans

Article abstract of DOI:10.1002/chem.201403523

Ethyl acetohydroxamate was efficiently arylated with diaryliodonium salts at room temperature under transition-metal-free conditions. The obtained O-arylated products were reacted in situ with ketones under acidic conditions to yield substituted benzo[b]furans through oxime formation, [3,3]-rearrangement, and cyclization in a fast and operationally simple one-pot fashion without using excess reagents. Alternatively, the O-arylated products could be isolated or transformed in situ to aryloxyamines or O-arylaldoximes. The methodology was applied to the synthesis of Stemofuran A and the formal syntheses of Coumestan, Eupomatenoid 6, and (+)-machaeriol B. Just add salt! A metal-free, room temperature arylation of ethyl acetohydroxamate, followed by an in situ reaction with ketones under acidic conditions yielded substituted benzo[b]furans in a fast and operationally simple one-pot fashion without using excess reagents (see scheme). Alternatively, the O-arylated products could be isolated, hydrolyzed in situ to aryloxyamines, or transformed to O-arylaldoximes. The efficiency of the methodology was demonstrated by the formal synthesis of several biologically active benzofurans.

Full text of DOI:10.1002/chem.201403523

DOI: 10.1002/chem.201403523
Communication
&
Synthetic Methods
Metal-Free One-Pot Synthesis of Benzofurans
Raju Ghosh, Elin Stridfeldt, and Berit Olofsson*[a]
Abstract: Ethyl acetohydroxamate was efficiently arylated
with diaryliodonium salts at room temperature under tran-
sition-metal-free conditions. The obtained O-arylated
products were reacted in situ with ketones under acidic
conditions to yield substituted benzo[b]furans through
oxime formation, [3,3]-rearrangement, and cyclization in
a fast and operationally simple one-pot fashion without
using excess reagents. Alternatively, the O-arylated prod-
ucts could be isolated or transformed in situ to aryloxy-
amines or O-arylaldoximes. The methodology was applied
to the synthesis of Stemofuran A and the formal syntheses
of Coumestan, Eupomatenoid 6, and (+)-machaeriol B.
The benzo[b]furan backbone is found in a variety of natural
products and pharmaceuticals, and the array of reported bio-
logical activities includes anti-inflammatory, analgesic, and anti-
fungal activities (Scheme 1A).[1] Furthermore, benzofurans have
recently been exploited in materials chemistry.[2]
Scheme 1. Benzofuran structures and synthesis.
The major interest in benzofuran applications has resulted in
the development of a wide range of synthetic methods to-
wards this target. Benzofurans are commonly synthesized by
transition-metal-catalyzed cross-coupling reactions of 2-halo-
phenols and alkynes, followed by cyclization.[3] Other metal-
catalyzed cross-coupling strategies have been reported as
well,[4] but despite the efficiency of metal-catalyzed reactions,
drawbacks remain that include high temperatures, prolonged
reaction times, the need for complex ligands, the use of excess
reagents, and trace-metal impurities remaining in the prod-
ucts.
Finally, ethyl acetohydroxamate can be converted to aryloxy-
amines by SNAr arylation with electron-deficient aryl fluorides,
followed by acid-promoted hydrolysis.[10] Buchwald and co-
workers recently reported a more general palladium-catalyzed
arylation of ethyl acetohydroxamate with aryl halides in the
presence of air-sensitive alkyl-arylphosphine ligands.[11] The
products were subsequently transformed into benzofurans in
one pot through O-arylketoximes and a [3,3]-rearrangement/
cyclization sequence.
Aryloxyamines are important precursors of O-aryloximes and
benzofurans.[5] They can be synthesized by the Cu-catalyzed ar-
ylation of N-hydroxyphthalimide with arylboronic acids, fol-
lowed by cleavage with hydrazine (Scheme 1B).[6] Ketoximes
with a-hydrogen atoms can be arylated under metal-catalyzed
conditions to give O-arylketoximes,[7] which can undergo an
acid-promoted [3,3]-rearrangement/cyclization sequence, close-
ly resembling the Fischer indole synthesis.[8] This strategy has
been employed in the synthesis of several biologically active
benzofurans.[9]
We have recently described the metal-free arylation of N-hy-
droxyimides with diaryliodonium salts under novel hydrolytic
conditions to yield aryloxyamines (Scheme 1B).[12] To obtain
benzofurans without having to isolate the aryloxyamines, we
took inspiration from Buchwald’s two-step route and set out
to develop a metal-free one-pot arylation of ethyl acetohydrox-
amate with diaryliodonium salts 1 and subsequent reaction of
intermediates 2 with ketones 3 to form benzofurans 4
(Scheme 1C).
Herein, we present our preliminary results on the first one-
pot arylation, hydrolysis, oxime formation, [3,3]-rearrangement,
and cyclization sequence to yield benzofurans in good yields
and short reaction times.
[a] Dr. R. Ghosh, E. Stridfeldt, Prof. B. Olofsson
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, SE-106 91 Stockholm (Sweden)
Fax: (+46)8-15-4908
The arylation of ethyl acetohydroxamate with diphenyliodo-
nium triflate (1a) to yield O-phenylated product 2a was opti-
mized at ambient temperature (Table 1). A solvent screening
with potassium tert-butoxide as base revealed that acetonitrile
E-mail: berit@organ.su.se
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403523.
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Table 1. Optimization of the arylation.[a]
Table 2. Arylation scope of ethyl acetohydroxamate.
Entry
1
X
Base
([equiv])
Solvent
Time
[h]
Yield
[%][b]
Entry
1
Salt 1
Product 2
Yield
[%][a]
([equiv])
1
2
3
4
5
6
7
8
9
10
11
12
13[c]
14[c]
15[c]
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.2)
1a (1.3)
1a (1.1)
1a (1.1)
1a (1.1)
1b (1.1)
1c (1.1)
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
OTs
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuOK (1.2)
tBuONa (1.2)
K2CO3 (1.2)
KOH (1.2)
tBuONa (1.3)
tBuONa (1.1)
tBuONa (1.1)
tBuONa (1.1)
tBuONa (1.1)
tBuONa (1.1)
THF
toluene
DMF
15
15
15
15
15
15
15
15
15
15
15
0.5
0.5
0.5
0.5
50
42
73
68
78
91
93
82
80
90
91
93
92
88
87
87
89
74
dioxane
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
3[b]
4
5
77
64
[a] Ethyl acetohydroxamate (0.25 mmol) and base were stirred in anhy-
drous solvent (1.5 mL) for 15 min at RT before addition of 1. [b] 1H NMR
yield with 1,3,5-trimethoxybenzene as internal standard. [c] 1 mL of sol-
vent was used.
6
7
8
78
51
81
was the best solvent (entries 1–6). Sodium tert-butoxide was
equally efficient as potassium tert-butoxide, whereas other
bases gave a slightly lower yield of 2a (entries 7–9). The reac-
tion proved as efficient with only 1.1 equivalents of salt 1a
and sodium tert-butoxide as base (entries 10 and 11), and a re-
action time of 30 min was sufficient to obtain 2a in excellent
yield (entries 12 and 13).
Finally, iodonium tetrafluoroborate 1b and tosylate 1c were
employed to examine the anion tolerance of the reaction. For-
tunately, salts with these anions also provided 2a in high yield,
which is important because a wide anion tolerance simplifies
the synthesis of substituted diaryliodonium salts.
[a] Isolated yields. [b] 1.3 equiv of salt and base, 1 h reaction time.
transfer in metal-catalyzed arylations and can serve as useful
The generality of this arylation was subsequently investigat- handles for further synthetic manipulations (see below). Ortho-
ed by employing differently substituted iodonium salts 1,[13] substituted aryl groups could be transferred in moderate
and high isolated yields were obtained with a variety of salts yields, as exemplified by the incorporation of the 2-fluorophen-
despite the volatility of the corresponding products
2
yl group in 2g (entry 7). Furthermore, heteroaryl salts could be
(Table 2).[11] Unsymmetric salts were used when this facilitated employed, and a pyridyl group was chemoselectively trans-
the synthesis of the salt, and complete chemoselectivity was ferred from unsymmetric salt 1j to give compound 2h in 81%
obtained in all cases.[14]
yield (entry 8).
The electron-deficient 4-nitrophenyl group was chemoselec-
With the optimized arylation conditions at hand, we envi-
tively transferred from unsymmetric salt 1d to give 2b in 89% sioned a sequential one-pot arylation and oxime ether forma-
yield (entry 2). Importantly, also the novel 4-methoxy product tion/rearrangement to form benzofurans 4 without the isola-
2c could be obtained in good yield by slightly increasing the tion of the volatile compounds 2. Buchwald and coworkers
amount of the reagents (entry 3), which is in contrast to our have reported the reaction of 2 with ketones in the presence
previous arylation of NÀO substrates to give N-aryloxyimides.[12] of HCl and water in refluxing dioxane to yield benzofurans.[11]
Electron-rich products are difficult to obtain by SNAr reactions
The feasibility of our one-pot strategy was first investigated
with hydroxylamine equivalents, and metal-catalyzed arylations by treating 2a with acetophenone (3a) under modified Buch-
of this substrate class failed or are low-yielding.[6,11]
wald conditions by using acetonitrile instead of dioxane
As expected, alkyl substituents were well tolerated (2d and (Scheme 2). This gratifyingly delivered benzofuran 4a in 91%
2e), and the bromo-substituted product 2 f was formed in yield through hydrolysis, O-aryloxime formation, [3,3]-rear-
good yield (entries 4–6). Bromide substituents are difficult to rangement, and cyclization.[8]
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Scheme 2. Benzofuran synthesis under modified Buchwald conditions.
Having demonstrated the solvent compatibility between the
arylation and the benzofuran formation, an optimization of the
second step in the envisioned one-pot reaction was performed
(Table 3). To our delight, benzofuran 4a was formed in an im-
pressive yield of 82% when the two steps were combined
(entry 1). The reaction time was screened and 2 h proved suffi-
Table 3. Optimization of the one-pot synthesis of benzofurans.[a]
Entry
3a
[equiv]
HCl source
Temp.
[8C]
Time
[h]
Yield
[%][b]
Scheme 3. Scope of the one-pot synthesis of benzofurans. [a] Longer reac-
tion time in step 2, see the Supporting Information.
1
2
3
4
5
6[c]
2.0
2.0
2.0
1.2
1.2
1.2
4 m in dioxane
4 m in dioxane
4 m in dioxane
4 m in dioxane
4 m in dioxane
37% (aq)
70
70
70
70
50
70
3
2
1
2
2
2
82
84
75
82
50
82
products 4b and 4c required a longer reaction time to reach
useful conversions.[15]
Next, variation of the ketone structure was explored, and
2,3-diphenylbenzofuran 4g was successfully obtained. Cyclo-
hexanone was an excellent substrate, delivering tricyclic prod-
uct 4h in 82% yield. Considering that the overall transforma-
tion consists of five steps (arylation, hydrolysis, oxime ether
formation, rearrangement, and cyclization), yields in this range
correspond to an average reaction efficiency of >95% per
step.
[a] Step 1: ethyl acetohydroxamate (0.25 mmol), base (1.1 equiv) and 1a
(1.1 equiv), see Table 1, entry 13. Step 2: 3a, H2O, and HCl were added at
RT and the vial was purged with argon. [b] 1H NMR yield with 1,3,5-trime-
thoxybenzene as internal standard. [c] No H2O was added.
cient (entries 2 and 3). The atom efficiency was improved by
reducing the amount of 3a to 1.2 equivalents (entry 4), while
lowering the temperature to 508C had a negative impact on
the yield (entry 5).
The one-pot reaction was subsequently utilized in the syn-
thesis of several biologically active benzofurans, without the
use of protective groups. Tetracyclic benzofuran 4i can be oxi-
dized in one step to Coumestan, which is the central core in
the Coumestans, some of which show estrogenic activity.[9b,16]
Ketones with unprotected hydroxyl groups were employed to
give phenolic compounds 4j and 4k. Benzofuran 4j can be
converted to Eupomatenoid 6, having antifungal, insecticidal,
and antioxidant activity, in one step.[9,17]
The amount of water was important, and reactions in un-
dried acetonitrile, without added water, delivered 4a in a poor
yield. To further simplify the protocol, the use of aqueous HCl
instead of a combination of HCl/dioxane and five equivalents
of water was investigated, and 4a was obtained in an equally
good yield (entry 6).
With these efficient, fast, and practical reaction conditions at
hand, the one-pot synthesis of benzofurans was applied to
a range of diaryliodonium salts 1 and ketones 3 (Scheme 3). By
variation of iodonium salts 1, important functional groups
such as nitro, trifluoromethyl, alkyl, and bromide were intro-
duced to yield products 4a–f. In agreement with previous re-
ports, benzofuran formation from the oxime ether intermedi-
ate was slow with electron-withdrawing substituents;[8d] hence,
Stemofurans are a subgroup of 2-arylbenzofurans with hy-
droxyl substituents, which show antifungal activity, and are
used in the treatment of respiratory disorders in traditional
medicine.[18] Stemofuran A (4k) was obtained in 80% yield,
which also constitutes a metal-free formal synthesis of (+)-ma-
chaeriol B, an antimicrobial and antimalarial agent.[19]
Finally, the arylation was combined with an acidic hydrolysis
at room temperature to provide aryloxyamine 5 in 81% yield
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Acknowledgements
This work was financially supported by the Wenner-Gren Foun-
dations and Carl Trygger Foundation.
Keywords: arylation
·
aryloxyamines
·
cyclization
·
diaryliodonium
rearrangement
salts
·
O-aryloximes
· sigmatropic
Scheme 4. One-pot synthesis of aryloxyamine 5 and aryloxime 6.
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The efficiency of the protocol is demonstrated by the syn-
thesis of Stemofuran A, and the formal syntheses of Coume-
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should find vast application in the synthesis of biologically in-
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Experimental Section
One-pot synthesis of benzofurans 4
Ethyl acetohydroxamate (0.5 mmol) was added to an oven-dried
re-sealable cap vial, dissolved in anhydrous CH3CN (2.0 mL) and the
vial was capped with a rubber septum. tBuONa (0.55 mmol) was
added in one portion at 08C and the mixture was stirred vigorous-
ly at RT for 15 min. The reaction vial was then submerged into
a water bath at ambient temperature and salt 1 (0.55 mmol) was
added in one portion (note: slightly exothermic reaction). The re-
action mixture was stirred vigorously at RT for 30 min. Ketone 3
(0.6 mmol) was then added and the vial was purged with argon
and submerged into a water bath at ambient temperature. HCl
(37% (aq), 2.5 mmol) was added dropwise through a volumetric
pipette. The vial was purged with argon, sealed, and stirred at RT
for 15 min and then stirred at 708C for 2 h. The reaction mixture
was diluted with diethyl ether (4 mL), quenched with NaOH (1m,
3 mL), extracted with diethyl ether, washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography using pen-
tane and Et2O, EtOAc, or CH2Cl2 as eluents to give benzofuran 4.
[14] For chemoselectivity investigations, see ref. [13e] and J. Malmgren, S.
Santoro, N. Jalalian, F. Himo, B. Olofsson, Chem. Eur. J. 2013, 19, 10334–
10342.
[15] Formation of the oxime ether was facile, and 30% of product 7 was iso-
lated despite a prolonged reaction time.
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Received: May 14, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Synthetic Methods
R. Ghosh, E. Stridfeldt, B. Olofsson*
&& – &&
Just add salt! A metal-free, room tem-
perature arylation of ethyl acetohydrox-
amate, followed by an in situ reaction
with ketones under acidic conditions
yielded substituted benzo[b]furans in
a fast and operationally simple one-pot
fashion without using excess reagents
(see scheme). Alternatively, the O-arylat-
ed products could be isolated, hydro-
lyzed in situ to aryloxyamines, or trans-
formed to O-arylaldoximes. The efficien-
cy of the methodology was demonstrat-
ed by the formal synthesis of several
biologically active benzofurans.
Metal-Free One-Pot Synthesis of
Benzofurans
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