Gold(I)-catalyzed rearrangement of 3-silyloxy-1,5-enynes: An efficient synthesis of benzo[b]thiophenes, dibenzothiophenes, dibenzofurans, and indole derivatives

Article abstract of DOI:10.1002/chem.201200314

With the IPr ligand (IPr=1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene) on gold(I) excellent yields in the benzanellation of 2-substituted thiophenes, benzothiophenes, pyrroles, benzofurans, and indoles were achieved. The 1-siloxybut-3-ynyl side chain

Full text of DOI:10.1002/chem.201200314

FULL PAPER
DOI: 10.1002/chem.201200314
Gold(I)-Catalyzed Rearrangement of 3-Silyloxy-1,5-enynes: An Efficient
Synthesis of Benzo[b]thiophenes, Dibenzothiophenes, Dibenzofurans, and
Indole Derivatives
A. Stephen K. Hashmi,*[a] Weibo Yang,[a] and Frank Rominger[a, b]
Abstract: With the IPr ligand (IPr=
1,3-bis-(2,6-diisopropylphenyl)imida-
zol-2-ylidene) on gold(I) excellent
yields in the benzanellation of 2-substi-
tuted thiophenes, benzothiophenes,
pyrroles, benzofurans, and indoles were
achieved. The 1-siloxybut-3-ynyl side
chains, incorporated in the anellation,
are easily accessible by the addition of
a propargyl metal reagent to a formyl
group and silylation of the alcohol.
This conveniently allows an anellation
at the position of the formyl group
under mild conditions. All reactions in-
volve a 2,3-shift of the side chain in the
anellation step and thus, provide an
easy access to specific substitution pat-
terns. Only in the case of 2-substituted
indoles with their highly nucleophilic 3-
position a direct hydroarylation with-
out shift is observed. On the other
hand, 3-substituted indoles give the
same products as 2-substituted indoles.
Then, a 3,2-shift in the indole ring
system has to be involved.
Keywords: alkynes · benzofurans ·
gold · heterocycles · pyrroles · silyl
ethers · thiophenes
Introduction
Gold-catalyzed[1] cyclizations that involve aromatic and het-
eroaromatic compounds and alkynes have proven to be very
successful in the efficient synthesis of bioactive compounds,
which is well documented by many publications during the
last decade.[2]
One of the reaction types observed in heterocyclic sys-
tems involves arenium intermediates that rearomatize by
a Wagner–Meerwein rearrangement, for example, a shift of
one of the substituents from the 3-position to the 2-position
of the heterocyclic framework A[3] and subsequent loss of
a proton or an opening of a three-membered ring in the
spiro intermediate of type B (Scheme 1).[4]
Scheme 1. 3,2-Shift in the furyl-derived Wheland-type intermediates pro-
posed by Kirsch and Schmalz.
readily available precursors. This method allowed the con-
venient synthesis of the otherwise not easily accessible 7-
substituted benzo[b]furans (Scheme 2).[7] The position of the
substituents in the product can be explained by the reaction
pathway. After the initial coordination of the gold catalyst
Similar 3,2-shifts have been observed in indole systems.[5]
The only example, for which a 2,3-migration was suggested,
is a pyrrole derivative with an acyl group on the 2-position
of the aromatic ring.[6] This acceptor substituent makes
a direct attack of the electrophile at the 3-position less feasi-
ble.
ꢀ
to the C C triple bond of the substrate 1 in intermediate C,
an attack at the most nucleophilic 2-position of the furan
We recently reported a new 2,3-shift in a Wheland-type
intermediate derived from a furan derivative, which led to
the formation of benzo[b]furans in excellent yields from
[a] Prof. Dr. A. S. K. Hashmi, 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
[b] Dr. F. Rominger
Crystallographic investigation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200314.
Scheme 2. Formation of 7-substituted benzo[b]furans, involving a 2,3-shift
of an alkyl group.
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Table 1. Optimization studies on the rearrangement of 3a.[a]
ring (D),[8] rather than a direct hydroarylation at the 3-posi-
tion of the furan, occurs. The attack at the 3-position would
position the Ar substituent at the 4-position of the benzo[b]-
furan product, which is not observed. This 5-endo-dig cycli-
zation to D is followed by a Wagner–Meerwein shift, leading
to E with a more stable carboxonium ion. Deprotonation
and protodeauration give the aromatic furan ring in F and
elimination of silanol creates the benzene ring in the final
product 2.[9]
The best catalyst for this transformation was the
[(IPr)AuNTf2] catalyst (NTf2 =bis(trifluoromethanesulfony-
l)imidate). The reactions proceeded conveniently at room
temperature in CH2Cl2 and no inert gas atmosphere was
necessary.
We now wanted to expand the synthetic impact of these
rare 2,3-shifts in five-membered heterocycles. This would
provide a convenient access to other anellated heterocyclic
systems, which also represent highly interesting targets. On
the other hand, from other reactions, like the gold-catalyzed
phenol synthesis, we had learned that a transfer to thio-
phenes, pyrroles, and related molecules might be challeng-
ing, if not impossible.[10]
Entry
Catalyst
[(PPh3)AuNTf2]
[(NAC)AuCl]/AgSbF6
[(SPhos)AuNTf2]
AuCl
AuCl3
Solvent
Time [h]
Yield [%]
1
2
3
4
5
G
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
24
24
24
24
24
24
24
24
24
24
20
12
73
37
traces
95
n.r.
traces
n.r.
68
R
A
6[b]
7
8
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
9
C
iPrOH
CH2Cl2
10[c]
ACHTUNGTRENNUNG
[a] Reaction conditions: substrate (100 mmol), [Au] (2 mol%), [Ag]
(2 mol%), iPrOH (1.1 equiv), CH2Cl2 (2 mL), RT, in air. The reaction
was monitored by TLC. [b] Substrate (200 mmol). [c] 408C. NAC=nitro-
gen acylic carbene. n.r.=no reaction.
the temperature to 408C does lead to catalyst deactivation
rather than acceleration (entry 10).
Then, other substrates were subjected to the optimal reac-
tion conditions from Table 1 ([(IPr)AuCl] (2 mol%),
AgNTf2 (2 mol%), RT, CH2Cl2; Table 2). With the thio-
phene ring and either a phenyl (3a), a 3-bromophenyl (3b),
Results and Discussion
The substrates were easily accessible by addition of
in situ formed propargylic organozinc or Grignard
reagents to heteroaromatic aldehydes and subse-
quent silylation of the secondary alcohol and Sono-
gashira coupling.
Table 2. Scope and limitations of AuI-catalyzed rearrangement of 3-silyloxy-1,5-
enynes 3.[a]
Initially, we chose 3a as a model substrate to ex-
plore the feasibility and efficiency of the desired
transformation. With the sulfur-containing thio-
phene ring, compound 3a belongs to the most diffi-
cult substrate class. If this molecule can be convert-
ed, the reaction should be successful for most of
the other substrate types as well. Table 1 outlines
the results of the optimization experiments. The
catalyst, employed in this process, played a crucial
role, with the gold(I) complex of the N-heterocy-
clic carbene (NHC) ligand IPr being the most effi-
cient catalyst. To our delight, this catalyst gave the
anticipated product 4a in 95% isolated yield
(entry 6). [(SPhos)AuNTf2] (SPhos=2-Dicyclohex-
ylphosphino-2’,6’-dimethoxybiphenyl) was also ef-
fective, providing the same product in 73% yield
Entry Substrate
Products
Time
[h]
Yield
[%]
1
3a
3b
4a 24
95
99
2
3
4b 12
3c
4c 24
72
after 24 h (entry 3). However, goldACTHNUGRTENUNG(III) chloride
was less effective than gold(I) in terms of yield
(entry 5). After identifying an appropriate catalyst,
we optimized other critical reaction parameters,
such as solvent and temperature. In particular, the
transformation was strongly influenced by the sol-
vent. Polar solvents (CH3CN, THF, and iPrOH)
were not suitable for this transformation (en-
tries 7–9). Furthermore, the temperature effect was
also investigated and it turned out that increasing
4
5
3d
3e
4d
2
98
70
4e 120
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Gold(I)-Catalyzed Rearrangement of 3-Silyloxy-1,5-enynes
Table 2. (Continued)
FULL PAPER
or a 4-nitrophenyl (3c) substituent on the alkyne
moiety very good yields were obtained (entries 1–
3). The structure of 4c was proven by X-ray crystal-
structure analysis (Figure 1a).[11] Even the combina-
tion of two thiophene rings in substrate 3d gave 4d
in 98% yield (entry 4). Only with the naphyl sub-
stituent in 3e, very slow conversion and a reduced
yield of 70% was observed (entry 5). Benzothio-
phenes reacted as well. Again, the combination
with either a phenyl (3 f) or a 3-bromophenyl (3g)
substituent on the alkyne was successful (entries 6
and 7). Interestingly, only with a thienyl group in
3h, the isomer of 4h, namely 5h, was also formed
in equal amount (entry 8). Compound 5h was un-
ambiguously characterized by X-ray crystal-struc-
ture analysis (Figure 1b).[11] All the reactions with
benzothiophenes were slow.
A pyrrole ring, in combination with a thiophene
ring on the alkyne in 3i, yielded 92% of the prod-
uct in a very fast reaction (entry 9). Switching to
the benzfuran-derived substrates with either a thien-
yl (3j) or a 3-bromophenyl (3k) substituent on the
alkyne moiety gave very good results as well (en-
tries 10 and 11). The characterization by X-ray crys-
tal-structure analysis was also possible for 4k (Fig-
ure 1c).
Entry Substrate
Products
Time
[h]
Yield
[%]
6
3 f
3g
4 f 144
45
7
8
4g 48
4h 12
5h 12
71
48
52
3h
9
3i
3j
4i
4j
1
3
92
88
10
Owing to the recent intensive research on gold-
catalyzed conversions of indoles,[12] we also included
these heterocycles in the investigation of our new
method. Indole systems can be converted equally
well (entries 12–15), but here, a highly interesting
selectivity switch was observed. 3l and 3m only
differ in the attachment to the indole ring. 3l repre-
sents the typical C2-linked substrate of this study
and the normally observed product 4l was formed
(entry 12). In the case of the indole system, with
the most nucleophilic center in the 3-position, this
is most easily explained by a direct electrophilic
attack of the activated alkyne at this position
(rather than a spiro intermediate and a 2,3-shift of
the alkyl group, as in the case of 3a–3k). Most sur-
prisingly, 3m provided the same product 4l
(entry 13, see also 1H NMR spectra in Figure 2).
This indicates that now a selective 3,2-shift of the
alkyl group occurs and a spiro-type intermediate
has to be involved in the transformation of 3m.
This unique behaviour was confirmed by the con-
version of both 3n and 3o, which gave the same
product 4n (entries 14 and 15).
11
12
3k
3l
4k 12
88
89
4l
4l
1.5
13
3m
1.5
72
14
15
3n
3o
4n
4n
1
1
98
55
The products 4b can be transformed by other
transition-metal-catalyzed reactions; one example is
the palladium-catalyzed Suzuki coupling of 4b.
Here, the mild ligand-free aqueous catalytic system,
which was developed by Liu and Yang,[13] was ap-
plied, providing 6 in a fast reaction with an excel-
lent yield of 98% (Scheme 3).
[a] Reaction conditions: substrate (100 mmol), [(IPr)AuCl] (2 mol%), AgNTf2
(2 mol%), iPrOH (1.1 equiv), CH2Cl2 (2 mL), RT, in air. The reaction was monitored
by TLC.
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A. S. K. Hashmi et al.
Overall, the short and mild route for the benzanellation
of heterocycles, starting from a simple formyl substitutent, is
a highly useful tool for organic synthesis.
Acknowledgements
W. Yang is grateful to the CSC for a fellowship. Gold salts were gener-
ously donated by Umicore AG & Co. KG.
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cif.
Conclusion
The 2,3-shift for the benzanellation of five-membered heter-
oarenes can be extended to the synthesis of benzo[b]thio-
phenes, dibenzothiophenes, dibenzofurans, and indoles. In
the synthesis of benzoindoles, a new synthetic convergence
allows the use of the more readily available 3-substituted
starting materials instead of the more expensive 2-substitut-
ed substrates. This indicates a different mechanism for the
2-substituted indole substrates that does not involve a spiro
intermediate, but a direct electrophilic attack at the 3-posi-
tion of the indole.
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Gold(I)-Catalyzed Rearrangement of 3-Silyloxy-1,5-enynes
FULL PAPER
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Received: January 29, 2012
Published online: && &&, 2012
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A. S. K. Hashmi et al.
Gold Catalysis
A. S. K. Hashmi,* W. Yang,
F. Rominger ................... &&&& — &&&&
Golden rings: Benzanellated heterocy-
cles are conveniently accessible by
a gold(I)-catalyzed intramolecular cyc-
lization. The tandem 5-endo-dig cycli-
zation/2,3-shift places the heteroatom
X in ortho position of the aryl group
on the newly formed benzene ring (see
scheme).
Gold(I)-Catalyzed Rearrangement of
3-Silyloxy-1,5-enynes: An Efficient
Synthesis of Benzo[b]thiophenes,
Dibenzothiophenes, Dibenzofurans,
and Indole Derivatives
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!