Intermolecular Desymmetrizing Gold-Catalyzed Yne–Yne Reaction of Push–Pull Diarylalkynes

Article abstract of DOI:10.1002/chem.201800360

Push–pull diaryl alkynes are dimerized in the presence of a cationic gold catalyst. The polarized structure of the applied starting materials enables the generation of a highly reactive vinyl cation intermediate in an intermolecular reaction. Trapping of the vinyl cation by a nucleophilic attack of the electron-poor aryl unit then leads to the selective formation of highly substituted naphthalenes in a single step and in complete atom economy.

Full text of DOI:10.1002/chem.201800360

A Journal of
Accepted Article
Title: Intermolecular Desymmetrizing Gold-Catalyzed Yne-Yne-
Reaction of Push-Pull Diarylalkynes
Authors: Vanessa Weingand, Thomas Wurm, Vanessa Vethacke,
Martin C. Dietl, Daniel Ehjeij, Matthias Rudolph, Frank
Rominger, Jin Xie, and A. Stephen K. Hashmi
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To be cited as: Chem. Eur. J. 10.1002/chem.201800360
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10.1002/chem.201800360
Chemistry - A European Journal
Intermolecular Desymmetrizing Gold-Catalyzed Yne-Yne-Reaction of
Push-Pull Diarylalkynes
Vanessa Weingand,[a] Thomas Wurm,[a] Vanessa Vethacke,[a] Martin C. Dietl,[a] Daniel
Ehjeij,[a] Matthias Rudolph,[a] Frank Rominger,[a] Jin Xie,[a] A. Stephen K. Hashmi[a],[b],
*
[a] M. Sc. V. Weingand, Dr. T. Wurm, B. Sc. V. Vethacke, B. Sc. M. C. Dietl, B. Sc. D.
Ehjeij, Dr. M. Rudolph, Dr. F. Rominger,[+] Dr. J. Xie, Prof. Dr. A. S. K. Hashmi
Organisch-Chemisches Institut
Heidelberg University
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
Keywords: gold catalysis, vinyl cations, naphthalenes, alkyne dimerization, push-pull
systems
Abstract: Push-pull diaryl alkynes are dimerized in the presence of a cationic gold
catalyst. The polarized structure of the applied starting materials enables the
generation of a highly reactive vinyl cation intermediate in an intermolecular reaction.
Trapping of the vinyl cation by a nucleophilic attack of the electron-poor aryl unit then
leads to the selective formation of highly substituted naphthalenes in a single step and
in complete atom economy.
In the field of gold catalysis[1] reactions in which diyne systems are applied as starting
materials are becoming increasingly importance.[2] While this development began with
cascade reactions in which one alkyne unit is transformed into a nucleophilic part as
relay for further transformations,[3] only recently direct reactions between two
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connected alkyne parts were in the focus. These systems give rise to high energy
intermediates such as, gold vinylidenes,[4] diaurated phenyl cations,[5] aurated vinyl
cations[6] and aurated phenyl cations,[7] intermediates that enabled valuable
downstream transformations in the corresponding catalytic cycles. So far, all of these
transformations were restricted to intramolecular processes and examples for an
intermolecular generation of these high energy intermediates from two reacting alkyne
units via gold catalysis were unknown. If two terminal alkynes are applied as substrates
for intermolecular reactions, instead of the formation of high energy intermediates,
head to tail couplings are observed,[8] a well-known methodology that is not specific for
gold catalysis and that is extremely prominent in the literature for a highly diverse set
of metal catalysts.[9] In contrast, reactions that involve metal-catalyzed dimerizations
of non-terminal alkynes are restricted to only a few examples. For example
diarylalkynes can undergo a rhodium-catalyzed dimerization towards naphthalene
derivatives in the presence of catalytic amounts of strong acids.[10] This process is
assumed to proceed via an oxidative addition of HX onto the metal center, insertion of
the alkyne into the Rh-H bond, CH-activation of the aryl-H bond followed by the
insertion of the second alkyne and a subsequent reductive elimination to the products.
In addition diarylalkynes are known to dimerize to azulene derivatives in the presence
of Pd, but yields are generally low and high loadings or even stoichiometric amounts
of metal are necessary.[11] In the presence of stoichiometric amounts of oxidant and
Cu as additive, some substrates form naphthalenes in the presence of Pd catalysts,
but under these conditions mainly 8,8--dihydrocyclopenta[a]indenes are obtained.[12]
Gold catalysts are known to dimerize non-terminal ynamides which gives rise to
cyclopentadiene derivatives in most cases.[13]
Inspired by our recent work on the generation of vinyl cations by means of
intramolecular alkyne-alkyne gold catalysis,[6] we envisioned that the intermolecular
reaction of diaryl alkynes might result in the formation of an intermediate vinyl cation
that, upon addition of one of the aryl units, would deliver naphthalene structures in
perfect atom economy (Scheme 1). Compared to the mentioned rhodium-catalyzed
protocol, a completely different mechanism would operate without a change of the
oxidation state of the metal and the accompanying need for scope-limiting acidic
additives that are needed for the generation of the active Rh(III) species. In addition a
selective formation of the intermediate cation from differently substituted diaryl alkynes
would allow access to naphthalene derivatives with alternating aryl units.
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Scheme 1: Proposed gold-catalyzed process.
An initial screening for the desired reactivity was conducted with push-pull diyne 1a, a
substrate that was selected due to its electronic nature, which we considered as ideal
for a potential reaction towards alternating naphthalene systems. Indeed with
[(IPr*)Au(NCMe)]SbF6 as catalyst, moderate yields of naphthalene 2a were observed
in C6F6 as inert solvent. Switching the counter ion to BArF24 (which turned out to be the
ideal counter ion for the intermolecular generation of phenyl cations)[7] delivered only
poor results. Changing the solvent to DCE turned out to be beneficial and a high yield
-
of 78% was obtained after one day with the SbF6 counter anion. Attempts to lower the
temperature to 80°C were unsuccessful and only incomplete conversions were
obtained, even after prolonged reaction times. A short ligand screening revealed that
the sterically bulky IPr* ligand[14] has to be favored to the smaller IPr ligand or
JohnPhos as representative for a Buchwald-type ligand. Finally, the reaction was
conducted in at higher concentration. In addition to a higher reaction rate, the yield of
89% turned out to be significantly better. In order to establish the connectivity of the
obtained naphthalene scaffold, single crystals of 2a were grown and analyzed by X-
ray diffraction.[15] The substitution pattern of the exclusively obtained product 2a can
be rationalized by the proposed mechanistic scenario (Scheme 1) combined with the
intrinsic polarity of the applied alkyne. The selectivity of the nucleophilic attack of the
alkyne is controlled by the stability of the intermediate cation, while the attack only
takes place at the more electrophilic position at the second alkyne which is activated
by the gold catalyst bound to the more nucleophilic carbon (Scheme 2). Based on this
interplay, alternating substituents can be selectively placed at the central naphthalene
core. In contrast, the control reaction with the Rh catalyst system introduced by Miura´s
group, in an unselective reaction delivered only 32% of product 2a, accompanied by
regioisomer 2a´ that was obtained in 37% (Scheme 3). This lack of selectivity can result
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from unselective insertions of either the alkyne into the Rh-H bond or the alkyne into
the intermediate rhodacycle.
Table 1: Screening with Substrate 1a
Entry Catalyst
Solvent
time T
[°C]
conversion yield
1
2
3
4
5
6
7
[(IPr*)Au(NCMe)]SbF6
1 ml C6F6 2 d
1 ml C6F6 5 d
1 ml DCE 1 d
1 ml DCE 5 d
1 ml DCE 5 d
100 100%
100 5%
57%[b]
0%
IPr*AuCl/NaBARF
[(IPr*)Au(NCMe)]SbF6
[(IPr*)Au(NCMe)]SbF6
[(IPr)Au(NCMe)]SbF6
100 100%
78%[b]
47%
29%
0%
80
56%
100 42%
100 18%
[(JohnPhos)Au(NCMe)]SbF6 1 ml DCE 5 d
[(IPr*)Au(NCMe)]SbF6
0.1
ml 16 h 100 100%
89%[b]
DCE
1
[a] Reactions were run in a 250 µmol scale. Yields were determined by H NMR
spectroscopy, hexamethylbenzene was used as an internal standard if not otherwise
noted. [b] isolated yield.
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better stabilized vinyl cation
MeO
CF3
F3C
OMe
nucleophilic position
electrophilic position
LAu
Scheme 2. Left: Solid state molecular structure of 2a; right: model to explain the
obtained selectivity.
Scheme 3: Rhodium-catalyzed transformation of 1a
After this optimization of the conditions, we focused on the scope of the dimerization
reaction (Table 2). Besides the CF3-group as electron withdrawing substituent (2a),
ester (2b), ketone (2c), triflate (2d) and halide moieties (2e) were tolerated well and
the corresponding products could be obtained in moderate to good yields. The latter
two deserve a special note as these are potential building blocks for further
derivatizations using cross coupling strategies. The tolerance of these groups can be
explained by the low tendency of the gold catalyst against oxidative addition. As a next
step, the electron-rich part of the diarylalkyne was varied. An unprotected phenolic
hydroxyl group was also tolerated well (2f). Higher substituted aryl groups were also
suitable (2f-2g), but a slight drop in yield was observed for starting materials 1i bearing
one of the methoxy groups in ortho-position, which can be rationalized by sterical
hindrance. Electron-rich heterocyclic systems like different thienyl groups (2j, 2k)
afforded the desired products in moderate yield, too. However, the indole substrate 1p
showed an unexpected reactivity. In this case the more nucleophilic carbon C3 of the
indole attacks the -activated triple bond, which ultimately leads to the formation of N-
methylcarbazole derivative 3p (Scheme 4). If instead of an electron-donating aryl unit,
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alkyl groups such as cyclohexyl or tert-butyl groups (1l, 1m) were used, no reaction
was observed, which can be rationalized by the much lower stabilization of an
intermediate vinyl cation. Tolanes with decreased polarization of the alkyne (1n, 1o)
gave a complex product mixture.
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Table 2: Substrate scope
R
R
EWG
5 mol% [(IPr*)Au(NCMe)]SbF6
DCE, 100°C
EWG
EWG
R
OMe
OMe
OMe
O
O
F3C
MeO
O
Ph
O
CF3
OMe
Ph
MeO
MeO
MeO
2a, 89%
2b, 75%
2c, 75%
OH
OMe
OMe
F3C
Br
TfO
CF3
Br
OTf
HO
2f, 70%
MeO
MeO
F3C
2d, 66%
2e, 47%
OMe
OMe
OMe
OMe
OMe
OMe
O
F3C
MeO
MeO
O
OMe
CF3
CF3
OMe
MeO
MeO
MeO
MeO
OMe
2g, 93%
2h, 90%
2i, 54%
OMe
S
S
F3C
F3C
CF3
CF3
S
S
2j, 41%
2k, 43%
limitations:
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N
CF3
CF3
5 mol% [(IPr*)Au(NCMe)]SbF6
DCE, 100°C
CF3
N
1p
N
CF3
3p, 57%
N
[Au] or H
H
via
CF3
N
[Au]
Scheme 4: Dimerization of indole substrate 1p
In conclusion, an efficient gold-catalyzed protocol for the synthesis of highly substituted
naphthalene derivatives is presented. A cationic gold complex enables the generation
of a highly reactive vinyl cation in an intermolecular reaction of two diaryl alkynes. The
method allows to build up complex polyaromatic structures in a single step from readily
available starting materials. Mechanistically, the methodology is orthogonal to known
strategies catalyzed by other transition metals, which not only enables a systematic
permutation of the substituents at the naphthalene core, but also allows the installation
of halide atoms for potential further transformations. Additional studies on the
exploitation of intermolecular gold-catalyzed alkyne dimerization are ongoing in our
laboratories.
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[15] CCDC 1572052 (2a) contain the supplementary crystallographic data for this
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Crystallographic Data Centre.
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TOC:
Tolan Wedding: The intermolecular and selective gold-catalyzed dimerization of
polarized tolan derivatives gives rise to highly substituted naphthalenes via reactive
vinyl cation intermediates. This methodology is superior to existing unselective
strategies catalyzed by other transition metals and offers an entry to naphthalenes with
a controlled substitution pattern of electron-rich and electron-poor aryl groups.
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