Metal-free oxidative cyclization of alkynyl aryl ethers to benzofuranones

Article abstract of DOI:10.1002/anie.201304813

Readily available phenols can be converted into substituted aryl alkynyl ethers, which react with an N-oxide as an oxidant and catalytic amounts of a Bronsted acid to provide benzofuranones. If non-terminal alkynyl ethers are applied, a 1,2-hydride shift takes place and phenyl acrylates are obtained. Thus activated alkynes can serve as α-oxy carbene precursors even in the absence of a metal catalyst. Copyright

Full text of DOI:10.1002/anie.201304813

Angewandte
Chemie
DOI: 10.1002/anie.201304813
Heterocycle Synthesis
Metal-Free Oxidative Cyclization of Alkynyl Aryl Ethers to
Benzofuranones**
Katharina Graf, Carmen L. Rꢀhl, Matthias Rudolph, Frank Rominger, and A.
Stephen K. Hashmi*
Dedicated to Professor Teruaki Mukaiyama
Recently, reactions of N-oxides with alkynes have attracted
significant attention; several groups were involved and many
synthetically useful transformations have been reported.[1] In
nearly all of the reactions gold catalysts are used as p-
activators for the triple bond. After oxygen transfer and
release of pyridine, a-oxo gold carbenes[2] are obtained as
intermediates (Scheme 1, upper part). These highly reactive
that a nitrogen-assisted protonation of the alkyne initiates the
reaction cascade.
Herein we present a new and unusual metal-free N-oxide
transformation that can even be performed without any
additives or with only catalytic amounts of an acid. Our initial
aim was to use alkynyl aryl ethers 1 (substrates that are easily
available from inexpensive phenol derivatives) for the gold-
catalyzed oxidative cyclization providing benzofuranone
derivatives 2 (Scheme 2). The target structure is of great
Scheme 1. Top: Gold-catalyzed generation of a-oxo carbenoids.
Bottom: Metal-free N-oxide/alkyne reaction with stoichiometric
amounts of acid.
Scheme 2. Overview of previous synthetic routes to benzofuranones
and our new approach.
species can be used to generate a diverse set of valuable target
molecules. Apart from these transition-metal-catalyzed reac-
tions only one report was published by the Gong group in
which a metal-free process for this kind of chemistry was
presented (Scheme 1, lower part).[3] For this particular trans-
formation stoichiometric amounts of MsOH turned out to be
crucial to promote the reaction, and the authors speculate
interest, since it is a subunit in many natural products.[4]
Recent approaches for the synthesis of benzofuranones use
2-hydroxyphenylacetic acid[5] or substrates derived from this
structure as starting materials.[6] However, these reactions
require harsh conditions (Scheme 2, path a). Alternative
strategies comprise the oxidation of benzofurans with N-
oxides or oxone (Scheme 2, path b).[7]
For an initial screening (Table 1), we applied alkynyl aryl
ether 1a which is predestined to form a carbenoid that is
[*] Dipl.-Chem. K. Graf, C. L. Rꢀhl, Dr. M. Rudolph, Dr. F. Rominger,[+]
Prof. Dr. A. S. K. Hashmi
À
prone to be attacked by a nucleophile or to undergo C H
Organisch-Chemisches Institut
insertion. The desired product 2a was detected by GC-MS in
43% yield following application of the well-established
combination of IPrAuCl and AgNTf2 (Table 1, entry 1). In
a series of experiments with different silver salts as halide
scavengers no strong influence was evident and yields ranged
from 31% to 48% (Table 1, entries 2–6). To our surprise even
better yields were obtained by the use of AgNTf2 in the
absence of a gold catalyst (Table 1, entry 7). Even more
interesting for us was the fact that HBF4 diethyl etherate was
also able to mediate a conversion, even when only catalytic
amounts of acid were applied (Table 1, entry 11). This is
remarkable, as to the best of our knowledge this is the first
case in which a metal-free intermolecular N-oxide/alkyne
reaction takes place with only catalytic amounts of an acid as
Ruprecht-Karls-Universitꢁt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-54-4205
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation.
[**] We thank Umicore AG & Co. KG for the generous donation of gold
salts. We dedicate this work to Professor Teruaki Mukaiyama in
celebration of the 40th anniversary of the Mukaiyama aldol reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304813.
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Table 1: Catalyst screening.
Table 2: Scope of the reaction.
Entry
1
Substrate
Product
Yield[a]
81%
Entry
Catalyst
Catalyst
loading
Yield[a]
1b
2b
1[b]
2[b]
3[b]
4[b]
5[b]
6[b]
7[b]
8[b]
9
IPrAuCl/AgNTf2
IPrAuCl/AgSbF6
IPrAuCl/AgOTs
IPrAuCl/AgOTf
IPrAuCl/AgPF6
IPrAuCl/AgBF4
AgNTf2
HBF4·OEt2
IPrAuCl/AgOTf
AgNTf2
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
10 mol%
10 mol%
10 mol%
10 mol%
43%
31%
43%
37%
40%
48%
55%
55%
70%
82%
86%
36%
2
3
51%
1c
1d
2c
complex
mixture
–
10
11
12
HBF4·OEt2
p-toluene-
sulfonic acid
TFA
4
5
42%
63%
1e
1 f
2e
2 f
13
14
10 mol%
–
26%
–
42%[c]
[a] Determined by GC analysis. [b] Under anhydrous reaction conditions
(dry glassware, molecular sieves). [c] Yield of the isolated product after
18 h.
a promoter. Increasing the catalyst loading had a positive
effect on all of the tested catalyst systems (Table 1, entries 9–
13). HBF4 diethyl etherate turned out to be the catalyst of
choice while other tested Brønsted acids were less effective
(Table 1, entries 12 and 13). Even in the absence of catalyst
a significant amount of product could be obtained but yields
were lower for this uncatalyzed transformation and the
reaction time was longer (Table 1, entry 14).
6
7
8
78%
68%
64%
1g
1a
2g
2a
Changing the N-oxide to 8-isopropylquinoline N-oxide or
3,5-dibromopyridine N-oxide did not improve the yield but
resulted in rather unselective transformations. Furthermore,
neither meta-chloroperoxybenzoic acid nor N-methylmor-
pholine N-oxide were suitable oxidants for this reaction. DCE
and benzene were tested as alternative solvents. Whilst DCE
showed slightly lower conversion, benzene and 1,4-dioxane
gave equally good results.
1h
1i
2h
2i
9
30%
83%
10
Next we evaluated the substrate scope of this trans-
formation (Table 2). It should be mentioned that interpreta-
tion of yields is not easy due to the fact that the starting
alkynyl aryl ethers were used directly after elimination from
the corresponding dichloro vinyl ethers and some of the
elimination reactions did not deliver totally pure starting
materials. (Unfortunately column chromatography was not
suitable for the purification of the terminal aryl alkynyl
ethers; thus the yields pertain to two steps.) All of the
reactions were performed under the optimized conditions
using HBF4 diethyl etherate (10 mol%) as the catalyst and
2,6-dimethylpyridine N-oxide (3) as the oxygen donor
(1 equiv). Substrate 1b, bearing an unsubstituted phenyl
group, smoothly delivered the corresponding benzofuranone
2b in high yield (Table 2, entry 1). Even when one of the ortho
positions was blocked, the expected product 2c was still
obtained (Table 2, entry 2). When both of the ortho positions
1j
2j
11
12
77%[b]
1k
1l
2k-a/2k-b (5:1)
17%
2l
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Table 2: (Continued)
(Table 2, entry 11). Attempts to perform the reaction in
Entry
Substrate
Product
Yield[a]
a bidirectional fashion turned out to be difficult as the starting
materials were unstable. However, product 2l could be
isolated in poor yields (Table 2, entry 12). Next we inves-
tigated diynes 1m–o as starting materials. Owing to the
second alkynyl moiety, these starting materials could alter-
natively follow a dual activation pathway in the presence of
a gold catalyst;[8] thus these compounds were transformed
with gold as well as with the Brønsted acid catalysts. No dual
activation pathway was observed with the gold catalysts;
instead the oxidation pathway took place, but yields were
lower than in the corresponding conversions with Brønsted
acid (Table 2, entries 13–15) for all three cases. Finally, we
wanted to evaluate the compatibility with other functional
groups. A chloro substituent in para position of the arene was
well tolerated and the corresponding product 2p could be
isolated in moderate yield (Table 2, entry 16). Aniline deriv-
ative 1q could also be converted in good yield but the ortho/
para selectivity was poor (Table 2, entry 17). In addition to
the NMR-based structure assignments, X-ray crystal structure
analyses for compounds 2l and 2n were conducted. The solid-
state structures (Figure 1) provide the final proof for the
formation of the benzofuranone structures.[9]
56%
13
28%[c]
1m
2m
37%
14
34%[c]
1n
2n
18%
15
16
10%[c]
1o
1p
2o
2p
43%
17
64%[b]
1q
2q-a/2q-b (2:1)
[a] Yields of isolated products. [b] Combined yield of both isomers;
isomers were separable. [c] Yields for reaction catalyzed by IPrAuCl/
AgNTf2.
were blocked (1d), only a complex mixture was obtained and
Figure 1. Solid-state molecular structure of 2l (left) and 2n (right).
Thermal ellipsoids at 50% probability.
À
no selective C H insertion of the benzylic position took place
(Table 2, entry 3). Shifting one of the blocking methyl groups
to the meta position (1e) restored good reactivity but yields
were slightly lower (Table 2, entry 4). A substrate with an
alkene unit (1 f) delivered no cyclopropanation product; once
again exclusive formation of benzofuranone 2 f was observed
(Table 2, entry 5). A tert-butyl group in ortho position was
also well tolerated and product 2g was obtained in a good
yield of 78% (Table 2, entry 6). The yield of isolated product
generated from test substrate 1a was slightly lower, which
might be explained by the instability of the starting material
(Table 2, entry 7). The even more electron-rich substrate 1h
could also be converted in reasonable yield (Table 2, entry 8).
Shifting to an electron-withdrawing trifluoromethyl group
(1i) led to a significant decrease in yield but once again the
interpretation is difficult as the starting alkynyl ether 1i
turned out to be fairly unstable (Table 2, entry 9). Starting
materials containing a naphthyl moiety proved to be more
stable and as a consequence yields of the final products were
high (Table 2, entries 10 and 11). For substrate 1j, bearing the
alkynyloxy group in the a-position of the naphthyl system,
only one regioisomer was formed, whereas in the case of
substrate 1k a mixture of isomers (2k-a, 2k-b) was obtained
in a 5:1 ratio favoring the a-attack of the naphthyl system
Our proposed mechanism for this transformation, which is
highly speculative, can be divided into the uncatalyzed and an
acid-catalyzed pathway (Scheme 3). For the uncatalyzed case
the alkyne can react as an electrophile with the N-oxide
without further activation. This is based on the high reactivity
of the alkynyl ethers due to the effect of the adjacent oxygen
atom which increases the electrophilicity at the internal
Scheme 3. Proposed mechanism (3=2,6-dimethylpyridine N-oxide).
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ethynyloxybenzene (100 mg, 847 mmol; 1.0 equiv) was added and the
resulting mixture was stirred at 808C. After completion of the
reaction after 5 h the crude product was adsorbed onto Celite and
subjected to flash column chromatography over silica gel with
petroleum ether (PE)/ethyl acetate (EA)/dichloromethane (DCM)
(40:1:1). The product obtained was a yellow oil (91.3 mg, 681 mmol,
81%). Rf (PE/EA/DCM 10:1:1) = 0.22; 1H NMR (300 MHz, CDCl3):
d = 3.74 (s, 2H), 7.05–7.17 (m, 2H, 7.27–7.37 ppm (m, 2H). The
spectroscopic data are in agreement with the data in reference [7a].
alkyne position to form intermediate I. In the next step the
pyridine is released and a highly reactive carbene intermedi-
ate II is generated which can then insert into the aryl–
hydrogen bond. A related mechanism was discussed by the
Zhang group for an in situ generated N-oxide (generated by
the oxidation of an aniline derivative with mCPBA) which
then reacted in an intramolecular fashion.[10] Attempts to trap
the free carbene intermolecularly with external alkenes only
resulted in the formation of unseparable mixtures.
For the catalyzed pathway the alkynyl aryl ether is
protonated by the acid, which increases the electrophilicity
and leads to the formation of the highly reactive ketenium
intermediate III. After attack of the N-oxide, intermediate IV
is formed which releases 2,6-dimethylpyridine and a proton to
generate the product 2.
Our proposed mechanism is endorsed by an experiment
with the non-terminal alkynyl aryl ether substrates 4. In this
case the 2,6-dimethylpyridine N-oxide 3 also attacks the more
electrophilic alkyne carbon next to the heteroatom to form
the highly reactive carbenoid intermediate. In contrast to the
previously described mechanism, these systems now have the
possibility of a competing 1,2-hydride shift onto the carbene
center which is the favored reaction step.[11] After this hydride
shift, phenyl acrylates 5 were obtained in 27% and 50% yield
(Scheme 4).
Received: June 4, 2013
Revised: July 26, 2013
Published online: October 7, 2013
Keywords: alkynes · benzofuranones · Brønsted acids · gold ·
.
oxidation
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In conclusion, we herein report a convenient metal-free
synthesis of benzofuranones using starting materials derived
from inexpensive phenol derivatives. The reaction proceeds
with only catalytic amounts of the Brønsted acid HBF4 diethyl
etherate and can even be performed without any additives.
2,6-Dimethylpyridine N-oxide was used as an oxidant and
oxygen donor. To the best of our knowledge this is the first
example of the generation of an a-oxy carbene in an
intermolecular reaction by application of an N-oxide without
the use of any additives or with only catalytic amounts of acid.
This demonstrates that highly activated alkynes can be used
as a-oxy carbene precursors even in the absence of a transition
metal. The easy accessibility of the starting materials and the
mild reaction conditions combined with the importance of
benzofuranone as target molecule make this new reaction
a useful advancement of recent synthetic approaches.
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Experimental Section
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Rudolph, F. Rominger, Adv. Synth. Catal. 2012, 354, 555 – 562;
General procedure: A round-bottomed flask was charged with
a
solution of the HBF4 diethyl etherate (13.7 mg, 84.7 mmol;
10 mol%) in 1.0 mL 1,4-dioxane. 2,6-Dimethylpyridine N-oxide
(104 mg, 847 mmol; 1.0 equiv) was added to this solution. Afterwards
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d) A. S. K. Hashmi, I. Braun, P. Nçsel, J. Schꢀdlich, M. Wieteck,
M. Rudolph, F. Rominger, Angew. Chem. 2012, 124, 4532 – 4536;
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2012, 124, 10785 – 10789; Angew. Chem. Int. Ed. 2012, 51, 10633 –
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Vilhelmsen, M. Rudolph, F. Rominger, Chem. Eur. J. 2013, 19,
1058 – 1065; g) M. M. Hansmann, M. Rudolph, F. Rominger,
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