Gold(I)-catalyzed formation of benzo[b]furans from 3-Silyloxy-1,5-enynes

Article abstract of DOI:10.1002/anie.201100989

Sport of kings: A new gold(I)-catalyzed transformation has been developed that occurs under mild conditions and proceeds by an expected substituent "castling" (see red and blue circles in scheme) to give efficient access to benzo[b]furans from the easy to

Full text of DOI:10.1002/anie.201100989

Communications
DOI: 10.1002/anie.201100989
Gold Catalysis
Gold(I)-Catalyzed Formation of Benzo[b]furans from 3-Silyloxy-1,5-
enynes**
A. Stephen K. Hashmi,* Weibo Yang, and Frank Rominger
Gold-catalyzed[1] cyclizations of aromatic and heteroaromatic
compounds with alkynes offer new ways for the efficient
construction of bioactive compounds, and have attracted
much attention in the last decade.
Recently, Kirsch et al.[2] developed an interesting method
for the synthesis of bicyclic formyl compounds. It is based on
the cyclization of 3-silyloxy-1,5-enynes under mild conditions
with gold(I) catalysts and iPrOH as an additive in a process
that involves a 6-endo-dig cyclization to the distal position of
the double bond and a pinacol rearrangement (Scheme 1).
The biphenyl derivative 3 is observed as a side product.
Figure 1. Furan derivatives 4 are structurally related to Kirsch’s sub-
strate 1. Ar=aryl, hetaryl; R=alkyl, aryl; TBDMS=tert-butyldimethyl-
silyl.
First experiments conducted with substrate 4a indicated
that a benzo[b]furan is formed in this conversion when
Gagoszꢀs[6] catalyst is used. Benzofurans represent an impor-
tant structural motif frequently found in a variety of bioactive
compounds (Scheme 2);[7] for example, 2-substituted benzo-
Scheme 1. Gold-catalyzed cyclization/pinacol rearrangement and the
competing reaction according to Kirsch et al.
Scheme 2. Bioactive compounds with a 7-aryl benzofuran core struc-
ture.[9]
Inspired by this intriguing study and in continuation of our
work on the application of furan substrates in synthesis,[3] we
investigated the reaction of compounds of type 4 (Figure 1).
As a consequence of both the short two-carbon tether
between the furan ring and the alkyne and the aryl substituent
on the alkyne, neither the gold-catalyzed synthesis of
phenols[4] nor related known reactions are possible.[5]
furans and their derivatives exhibit a broad range of biological
activities, such as their antineoplastic, antiviral, antioxidative,
and anti-inflammatory properties. As a result, a number of
routes leading to 2-substituted benzo[b]furans have been
described in the literature;[8] however, currently no general
synthetic methodology for the 7-substituted benzo[b]furans
exists, especially for 7-aryl benzofurans. Herein we report our
findings on how to gain access to the desirable 7-aryl
benzofurans by an unexpected substitutent “castling” proce-
dure.
Since the reaction time of 42 h and the yield of 87% were
not satisfactory, we optimized the catalysis conditions
(Table 1). While the new NAC–gold catalysts[10] (NAC =
nitrogen acyclic carbene) gave no significant improvement
(Table 1, entries 2 and 3) and simple gold chlorides delivered
very low yields (Table 1, entries 4 and 5), the N-heterocyclic
carbene (NHC) ligand 1,3-bis(2,6-diisopropylphenyl)imida-
zol-2-ylidene (IPr) afforded an improved yield of 91% after
only 1 h reaction time (Table 1, entry 6). Decreasing the
[*] Prof. Dr. A. S. K. Hashmi, M. Sc. W. Yang, Dr. F. Rominger[+]
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)711-685-4205
E-mail: hashmi@hashmi.de
[+] Crystallographic investigation
[**] W.Y. is grateful to the CSC (Chinese Scholarship Council) for a
fellowship. Gold salts were generously donated by Umicore AG &
Co. KG.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100989.
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Angew. Chem. Int. Ed. 2011, 50, 5762 –5765

Table 1: Optimization studies on the rearrangement of 4a.[a]
The connectivity of 5a can easily be explained by the
mechanism[13] depicted in Scheme 3. After coordination to the
triple bond (A),[14] the gold catalyst induces an electrophilic
Entry Catalyst
t [h] Yield [%]
1[b]
2[c]
3
4
5
[Ph3PAuNTf2]
42
3
48
42
42
1
8
48
1
87
58
68
19
23
91
93
18
[NACAuCl]/AgSbF6
[NACAuCl]/AgNTf2
AuCl
AuCl3
6
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgNTf2
[MePhosAuCl]/AgNTf2 24
AgNTf2
7[d]
8[e]
9[f]
10
11
12
85
92
n.r.
Scheme 3. Proposed mechanism for the gold(I)-catalyzed rearrange-
ment of the substrate 4a to the 2,7-disubstituted benzo[b]furan 5a.
42
48
p-TsOH
decomposition of the substrate
[a] Reaction conditions: Substrate (200 mmol), [Au] (2 mol%), [Ag]
(2 mol%), 1.1 equiv iPrOH, CH2Cl2 (3 mL), RT, in air. The reaction was
monitored by TLC. [b] Substrate (300 mmol). [c] Substrate (100 mmol).
[d] 0.5 mol% of catalyst. [e] 0.1 mol% of catalyst. [f] Without iPrOH. Tf=
trifluoromethanesulfonyl, n.r. =no reaction.
attack at the most nucleophilic position of the furan ring, the
2-position (B). After this 5-endo-dig cyclization, a Wagner–
Meerwein shift delivers the intermediate C with a more stable
carboxonium ion. Rearomatization of the furan by deproto-
nation and protodeauration delivers D, and a subsequent
aromatization by elimination of silanol affords the final
product 5a.
Crucial for the substituent “castling” is the selective
migration of the sp3-carbon atom rather than the sp2-carbon
atom in the spiro intermediate B, which probably originates
from stabilization of the positive charge in the transition state
of the 1,2-shift of the oxygen atom from the 2- to the 3-
position (carboxonium-like stabilization). Other gold-cata-
lyzed conversions involving furan-derived arenium intermedi-
ates have so far only shown a 1,2-shift from the 3- to the 2-
position in E[15] or a rearomatization by opening of a three-
catalyst loading to 0.5 mol% gave a respectable 93% yield of
the product after 8 h (Table 1, entry 7). With only 0.1 mol%
of catalyst, the yield dropped to 18% after 48 h, no more
conversion was observed after that time (Table 1, entry 8).
Without iPrOH as the additive, the yield was reduced by 6%
(Table 1, entry 9). An even better yield of 92% was obtained
with the phosphane ligand MePhos, but the reaction needed
24 h (Table 1, entry 10). Control experiments with silver(I)
gave no conversion (Table 1, entry 11), while with p-toluene-
sulfonic acid (p-TsOH) the usual slow decomposition of the
furan was observed (Table 1, entry 12).
Initially one could have expected the benzofuran to be the
product of a normal hydroarylation of the furan ring in the 3-
position[3b] and a subsequent aromatization by elimination of
silanol.[11] This would deliver the 2,4-disubstituted benzofuran
6a. A safe assignment of the structure of anellated disub-
stituted benzofurans by NMR spectroscopy is difficult, but
more reliable results were obtained by X-ray crystal structure
analysis of the benzofuran product.[12] Thus, the 2,7-disubsti-
tuted structure of 5a was proven unambiguously (Figure 2).
membered ring in the spiro intermediate of type
F
(Scheme 4).[16]
Apart from the intriguing mechanism, we were also
interested in the scope of this conversion. A series of
substrates 4a–4i was easily available by the reaction of
furfurals with propargyl bromide and zinc, silyl protection of
Figure 2. Left: Conceivable structure of benzofuran 6a. Middle: Solid-
state molecular structure of 5a. Right: Solid-state molecular structure
of the sulfur-containing product 5i. Thermal ellipsoids at 50%
probability.
Scheme 4. Furyl-derived Wheland-type intermediates according to
Kirsch et al. and Schmalz and co-workers. Top: R1 =aryl, alkyl;
R2 =alkyl; R3 =aryl, alkyl; bottom: R1 =aryl, alkyl; R2 =aryl, alkyl;
Nu=R3O.
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Communications
Table 2: Scope and limitations of the gold(I)-catalyzed rearrangement of 3-silyloxy-
example, reactions with substrates bearing either
electron-rich or electron-poor aryl-functional groups
on the alkyne moiety proceeded smoothly and
delivered the products in high yields (Table 2,
entries 1–5). Noticeably, even the sulfur-containing
thiophene substituent on the alkyne could be per-
fectly converted after 12 minutes without any sign of
catalyst deactivation (Table 2, entries 6 and 9). This is
one of the few conversions of a low-valent sulfur-
containing compound by gold catalysis.[5a,17] The X-ray
crystal structure of 5i again confirms the migration of
the substituent of the furan ring from position 2 to 3
(Figure 2).[12] Extended p systems such as the naph-
thyl substituent are tolerated and don’t influence the
relative migration aptitude (Table 2, entry 7). The two
examples containing bromoarenes (Table 2, entries 2
and 8) highlight the high functional-group tolerance
of the gold catalyst and the orthogonality to palladium
catalysts.[18]
In conclusion, we have developed a novel gold(I)-
catalyzed rearrangement reaction under mild condi-
tions, which provides a rapid and efficient access to
benzo[b]furans from the simple, readily available 3-
silyloxy-1,5-enynes. Further studies to probe the
mechanism of this transformation and extensions of
this chemistry towards thiophene and other hetero-
cycles can be easily envisioned, and are being
currently explored in our laboratory.
1,5-enynes.[a]
Entry Substrate
Product
t
Yield
[min] [%]
1
2
60
40
91
92
3
4
5
120 93
240 91
180 81
Received: February 9, 2011
Published online: May 9, 2011
6
7
12
95
Keywords: alkynes · carbenes · furans · gold ·
heterocycles
.
180 86
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