Gold-Catalyzed Formal Cyclisation/Dimerization of Thiophene-Tethered Diynes

Article abstract of DOI:10.1002/chem.201700061

A new pathway in dual gold-catalyzed reaction of thiophene-tethered diynes has been identified. A series of fully conjugated alkynyl-substituted benzothiophenes and benzofurans was obtained by a formal cyclisation/dimerization sequence. All the products are fluorescent, owing to their extended conjugation. The mechanistic studies have been carried out, suggesting that gold acetylides take part in this transformation.

Full text of DOI:10.1002/chem.201700061

A Journal of
Accepted Article
Title: Gold-Catalysed Formal Cyclisation/Dimerization of Thiophene-
Tethered Diynes
Authors: Svetlana Tšupova, Max M. Hansman, Matthias Rudolph,
Frank Rominger, and A. Stephen K. Hashmi
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To be cited as: Chem. Eur. J. 10.1002/chem.201700061
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10.1002/chem.201700061
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Gold-Catalysed Formal Cyclisation/Dimerization of Thiophene-Tethered Diynes
Svetlana Tšupova,[a] Max M. Hansmann,[a] Matthias Rudolph,[a] Frank Rominger,[a] A. Stephen K.
Hashmi*.[a],[b]
[a] M. Sc. Svetlana Tšupova, M. Sc. M. M. Hansmann, Dr. M. Rudolph, Dr. F. Rominger,[+] Prof.
Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Universität Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)-6221-54-4205
E-mail: hashmi@hashmi.de
Homepage: http://www.hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science, King Abdulaziz University
Jeddah 21589 (Saudi Arabia)
[+] Crystallographic investigation
[**] The authors thank Umicore AG & Co. KG for the generous donation of gold salts. The ST and
MMH are grateful to the Fonds der chemischen Industrie for a Chemiefonds scholarship and MMH
to the Studienstiftung des deutschen Volkes.
Keywords: Alkynes, arenes, furans, gold, thiophenes
Abstract
A new pathway in dual gold-catalysed reaction of thiophene-tethered diynes has been identified. A
series of fully conjugated alkynyl-substituted benzothiophenes and benzofurans was obtained by a
formal cyclisation/dimerization sequence. All the products are fluorescent, owing to their extended
conjugation. The mechanistic studies have been carried out, suggesting that gold acetylides take part
in this transformation.
Introduction
Gold catalysis has received considerable attention in the last decades.[1] A new reactivity pattern in
the gold catalysed cycloisomerisation of diynes was recently identified by the group of Zhang and
ours.[2] It was entitled dual activation, since two gold centers activate one single molecule of the
substrate simultaneously – one via σ-bonding to a terminal alkyne and another via π-complexation to
the second alkyne group. This double activation leads to the formation of highly reactive species –
mono aurated gold vinylidene or diaurated arene cation derivatives are obtained (Scheme 1).
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Scheme 1. Differerent cyclisation modes for dual gold catalysed diyne reactions.
Different initial cyclisation modes were observed for diynes incorporated into varying aromatic
backbones: benzenes[3] and 3,4-diethynylthiophenes as backbones[4] followed a 5-endo cyclisation
pathway forming aurated gold vinylidene intermediates (Scheme 1, A-type intermediate), 2,3-
diethynylthiophenes[5] and vinyl bound diynes[6] initiate 6-endo cyclisations (Scheme 1, B). Both types
of intermediates are reacting rapidly via C-H insertion reactions in an intramolecular manner or with
the solvent.[7]
Among the dialkynylthiophene cyclisations, we already explored C-H activations for different
substituents on the internal alkynes. As can be seen from Scheme 2, formation of 5 membered rings
in the second step of the cyclisations are preferred but a cyclobutene formation was also possible in
special cases if no C-H group suitably situated to obtain 5-membered ring is available (Scheme 2, d).
In continuation of these studies we considered aryl groups at the internal alkyne as well. The potential
intermediates also lack the possibility of -insertion which might contribute to the discovery of new
reaction pathways (Scheme 2, f). This contribution summarizes the chemistry of these starting
materials in dual gold catalysis.
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[Au]
[Au]
[Au]
Initial cyclisation
(a)
[Au]
6-endo
X
X
X
R
R
[Au]
R
[Au]
Second cyclisation via C-H activation
[Au]
[Au]
C-H activation
C-H activation
C-H activation
1
1
5
4
(b)
(c)
(d)
X
X
X
X
X
X
X
[Au]
[Au]
[Au]
[Au]
C-H activation
1
1
5
4
(e)
X
5
[Au]
[Au]
X = S or O
[Au]
(f)
Is
or
possible?
X
X
[Au]
[Au]
[Au]
Scheme 2. Reported thiophene and furan cyclisation pathways and the potential intermediates
addresed in this contribution.
Results and Discussion
Initial experiments were conducted with aryl substituted compound (1a) in the presence of a dual
activation catalyst.[8] Indeed the clean formation of one major product was detectable by TLC. Full
characterisation of the isolated product based on 2D-NMR data revealed the formation of a non
symmetric cyclisation/dimerisation product 2. While one of the diyne systems rearranged to the
aromatic core a second starting molecule is connected via the former terminal alkyne without a further
cyclization (Scheme 3).
Scheme 3. Initial observation.
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An optimization of the reaction conditions revealed DAC NTf2 in toluene at 80°C being the best
catalyst system (see ESI). Under these conditions we explored the scope of the transformation by
variations of the aryl substituent as well as the heterocyclic backbone (Table 1). Thiophenes, bearing
electron-donating groups on the phenyl moiety gave better results than the phenylacetylene derivative
(Entries 1 and 3 vs. 2). In agreement with this behavior, the reaction of para-fluoro-substituted
compound 1d was less clean, furnishing the product in only 25% yield (Entry 4). Furan backbones
were well tolerated and both applied substrates for this transformation led to the formation of cyclised
dimers in good yields (Entries 5-6). For benzothiophenes overall faster conversions were obtained and
in all cases the products were obtained in high yields (Entries 7-9). All of the obtained products show
fluorescence in solution. The absorption and emission spectra of two representative compounds (2a
and 2h) are depicted in Figure 1. The compounds show an emission maximum at 388 and 412 nm
with a determined quantum yields of 11.4% and 23.1% respectively.
Table 1. Scope of the dimerization reaction of substrates 1
Product
Entry
Diyne 1
X
R
Time
2
Yield
62 %
48 %
71 %
25 %
52 %
75 %
81 %
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
S
S
Me
H
4 h
5.5 h
6 h
2a
2b
2c
2d
2e
2f
S
OMe
F
S
18 h
4 h
O
O
S
H
Me
H
6 h
1g
2.5 h
2g
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8
9
1h
1i
S
S
Me
2 h
2h
2i
70 %
56 %
OMe
2.5 h
UV emission spectra of 2a and 2h
18
16
14
12
10
8
compound 2h
compound 2a
6
4
2
0
360
410
460
510
560
610
Wavelength, nm
UV absorbtion spectra of 2a and 2h
0,11
0,1
compound 2h
compound 2a
0,09
0,08
0,07
0,06
0,05
0,04
0,03
300
400
500
600
700
Wavelength, nm
Figure 1. UV spectra of compounds 2a and 2h
Fortunately, crystals suitable for X-ray analysis were obtained by slow diffusion of pentane into a
solution of 2h in CD2Cl2. The result further verifies the right assigned connectivity. Interestingly, the
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solid-state molecular structure of compound 2h shows a nearly perfect planar orientation of the
fluorenothiophene-alkyne-benzothiophene moieties with optimal overlap for π-conjugation (only the
p-tolyl moieties are slightly twisted out of plane). As depicted in Figure 2, a cyclisation/dimerisation
product 2h was obtained as single product.[9]
Figure 2. Molecular structure of 2h in the solid state.
The very high substrate sensitivity of this transformation was even more pronounced after swapping
the terminal and non-terminal alkyne substituents in the starting materials. While several of the
inversely substituted thiophenes were screened, the reaction only occurred with fluoro substituted
starting material 3a leading to an isolable product in low yield (Entry 1, Table 2). The corresponding
furan substrates 3b-3d showed clean reactions again, yielding the desired cyclisation-dimerisation
products in good yields (Entries 2-4). Both general motifs 2 and 4 might be useful structural units for
the application in molecular electronics such as semiconductors.[10]
Table 2. Scope of the dimerization of substrates 3
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Starting material
Product
Entry
Time
3
X
S
R
4
Yield
15 %
75 %
65 %
73 %
1
2
3
4
3a
3b
3c
3d
F
H
18 h
3 h
3 h
3 h
4a
4b
4c
4d
O
O
O
OMe
F
With one experiment we addressed a possible synthesis of hetero-dimers. An equimolar mixture of 1a
and 1c was treated with gold catalyst under standard reaction conditions. As a result, 13% of 2a, 25%
of 2c and an inseparable mixture of two compounds (25% combined) was isolated. The mass spectrum
indicated that this mixture is composed of the two conceivable hetero-dimers, the ration of the two
dimers was estimated to be 3:2 from the 1H NMR integrals.
Based on the connectivity of the product, one could compare the formation of the cyclisation-
dimerisation products with the previously reported hydroarylating cyclisation of phenyl diynes
bearing two terminal alkynes (Scheme 4).[2a]
Scheme 4. Relationship between observed cyclisation and previously reported one.
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In that case the addition of a solvent molecule took place ether in α- or β-position of the formed
naphthalene systems dependent on the mode of activation of the diyne: while -activation by one gold
center delivered the α product, dual σ,π-activation led to the formation of the β-product. Based on the
relationship of the products a -activation of the terminal alkyne in the applied thiophene diyne
substrate with cationic gold could initiate the cyclisation under formation of an intermediate aryl
cation A, which could be attacked by either a -activated gold acetylide or a terminal alkyne unit from
the starting material, giving rise to B and the product after protodeauration (Scheme 5, path 1). While
one cannot exclude this pathway, our studies on the use of dual activation catalysts imply that acetylide
initiated cyclizations are highly favored for this catalysts.[8] Thus the formation of a diaurated species
A´ followed by addition of an alkyne/ acetylide must be considered as well (Scheme 5, path 2).
Alternatively, according to a report by Zhang and coworkers, first a gold catalysed head-to-tail
coupling of the terminal alkynes of two starting materials[11] might occur under formation of enyne C.
A subsequent cyclisation of the obtained vinyl gold intermediate could also give rise to the final
product after deauration (Scheme 5, path 3).
Scheme 5. Plausible mechanistic pathways.
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This formation of an alkynyl-arene bond progresses via the electrophilic attack of a gold-generated
aryl cation at either the alkyne or the aurated alkyne. Thus it is redox neutral and nicely complements
the oxidative methods reported by the groups of Waser[12a] and Nevado.[12b]
To obtain further insight into the complex mechanistic puzzle, several experiments were conducted
next. An attempt to trap the aryl-cation A/A´ from pathway 1 or 2 by performing the reaction in the
presence of three equivalents of methanol failed. Only the hydration of the terminal alkyne
(proceeding probably via acetal formation with successive hydrolysis) occurred in this reaction giving
rise to 5 (Scheme 6, eq. 1). When the reaction was performed in the presence of heptyne (5 eq.), the
product of the addition of heptyne to the terminal triple bond of the substrate was isolated, which
would be in accordance to pathway 3. However it is noteworthy that no further cyclisation of enyne 6
was observed, neither when the reaction time was extended, nor when 6 was resubjected to the gold
catalyst (Scheme 6, eq. 2). To test further if pathway 3 represents a plausible reaction mechanism, the
postulated intermediate 7 (which was prepared by an addition/elimimination sequence of the lithiated
alkyne to the furyl ketone) was independently prepared. To our surprise not even a trace of conversion
was monitored for compound 7 under the normal conditions (Scheme 6, entry 3). Even more
unexpected is the fact, that in the presence of even small amounts of 7, the conversion of 1a to 2a was
inhibited. Only when the gold loading was higher than the loading of 7, 1a was transferred to the
product (Scheme 6, entry 4). This indicates that enyne 7 is not an intermediate of the reaction
mechanism. This might be attributed to the ability of enyne 7 to function as ligand for cationic gold
to act as a sort of “gold sponge” to absorb the catalytically active free cationic gold species. Despite
this fact still a cyclization might occur directly from the aurated intermediate, but outcome of the
crossover experiment from eq. 2 makes this unlikely as in this case a further cyclization should also
be monitored.
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Scheme 6. Mechanistic experiments.
Figure 3. Molecular structure of 8 in the solid state.
When a mixture of substrate 1a and its corresponding gold-acetylide 8 (Figure 3)[9] (4:1) was subjected
to standard catalytic conditions, product 2a was formed smoothly. The yield was comparable to that
of the standard experiment. The same reaction in the absence of cationic gold did not proceed (Scheme
6, eq. 5). However, when acetylide 9 was used, only an equilibration of acetylides occurred (Scheme
6, eq. 6). The formation of traces of enyne products might in this case contribute to the catalyst
deactivation again. The transformation of 1a into 2a in the presence of 5 mol% of IPr*AuCl/AgNTf2
as a catalyst, the reaction did not proceed. However, when 1a as treated with IPr*AuCl/AgNTf2 in the
presence of 8, the product formation could be observed. Taking into account that IPr* ligated gold is
less prone to the formation of gold acetylides (IPr*AuCl and 1a yielded in only 16% of the
corresponding acetylide), we can suggest that gold acetylides take part in the catalytic cycle.
The results of the deuterium labeling experiments are shown in the Scheme 7. When a deuterium
labeled starting material 1a was used in the reaction, 94% deuterium incorporation at the position 6
of the benzothiophene scaffold was observed. Position 4 suffered more from scrambling. In
accordance with that, the conversion of unlabeled 1a with DAC NTf2 in the presence of D2O led to a
deuterium incorporation of 80% in position 4 and 21% in the position 6. The unreacted starting
material contained 54% D. The results of the labeling experiments are not easy to interpret but the
difference between the two newly formed protons gives a hint that while the 4 position is most likely
transferred by the common catalyst transfer from a substrate molecule onto the aurated intermediate,
due to the high degree of deuterium incorporation a more direct process should be involved for the
position directly next to the newly incorporated alkyne. Thus a direct 1,2-addition of a deuterated
alkyne onto the aurated phenyl cation intermediate is more likely than the addition of an acetylide. In
this case exchange processes with the acetylide should at least reduce the labeling degree.
Unfortunately the labeling experiments cannot completely rule out that pathway 1 operates, as in this
case also a high degree of deuterium would be expected for the position next to the alkyne.
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Scheme 7. Deuterium labeling experiments.
Conclusion
In conclusion, we have further explored the reactivity of thiophene-based diynes under dual gold
catalyzed conditions. Thiophenes with aryl alkynes as starting materials give rise to highly interesting
fluorescent dimers in a yet unknown pathway for this activation mode. Despite intense efforts, the
mechanistic picture is still vage, but from the results of earlier studies and the mechanistic
investigations herein, most possible a pathway initiated by a 6-endo-cyclization followed by a direct
addition of the alkyne to the aryl cation takes place.
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