Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds Under π-Acid Catalysis

Article abstract of DOI:10.1002/ejoc.202000623

The reactivity of 7-alkynycycloheptatrienes tethered to an aryl group under π-acid catalysis has been studied. A variety of useful cyclic products were synthesized via Au(I)-catalyzed skeletal reorganization, Cu(II)-catalyzed hydroarylation, or Br?nsted acid-catalyzed tandem hydroarylation/Friedel-Crafts reaction. We also report a rare type of skeletal reorganization involving the 1,3-acetonide tether in the presence of a univalent cationic Ga(I)⁺ complex.

Full text of DOI:10.1002/ejoc.202000623

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds
Under π-Acid Catalysis
Authors: Marie Vayer, Christophe Bour, and Vincent Gandon
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000623
Link to VoR: https://doi.org/10.1002/ejoc.202000623
01/2020

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Exploring the Versatility of 7-Alkynylcycloheptatriene Scaffolds
Under -Acid Catalysis
Marie Vayer,[a] Christophe Bour,*[a] and Vincent Gandon*[a,b]
Abstract: The reactivity of 7-alkynycycloheptatrienes tethered to an
aryl group under π-acid catalysis has been studied. A variety of useful
cyclic products were synthesized via Au(I)-catalyzed skeletal
reorganization, Cu(II)-catalyzed hydroarylation or Brønsted acid-
catalyzed tandem hydroarylation/Friedel-Crafts reaction. We also
of a fluxional nonclassical Au-stabilized 9-barbaralyl cation.[9] On
the other hand, such compounds give different type of products
when treated by a hard Brønsted or Lewis acid. The group of
Kitagawa
described
the
rearrangement
of
7-alkynylcycloheptatriene derivatives into phenylallenes under
harsh acidic conditions (Eq. 3).[10] This reaction likely proceeds
through disrotatory 6π electrocyclization of the cycloheptatriene
moiety into the norcaradiene form, protonation of the alkyne into
a vinyl carbocation, ring-opening of the cyclopropyl moiety to give
a Wheland-type intermediate and regeneration of the catalyst by
proton elimination. Under hard Lewis acidic conditions, the allene
can be trapped by a pendant aryl group to give a hydroarylation
product (Eq. 4).[11]
report
a rare type of skeletal reorganization involving the
1,3-acetonide tether in the presence of a univalent cationic Ga(I)+
complex.
Introduction
π-Lewis acid catalysis has emerged as a powerful tool for the
construction of valuable building blocks through alkyne-, alkene-
or allene-activation.[ 1 ] Because the outcome of the skeletal
reorganization of an acyclic polyunsaturated compound is
critically dependent on the nature of the catalyst used, π-Lewis
acid catalysis is perfectly suited for the Diversity Oriented
Synthesis of complex molecular architectures that are present in
natural products, pharmaceuticals, agrochemicals, or materials.[2]
The rich diversity observed in π-Lewis acid catalyzed reactions
can be related to subtle effects influencing the mechanism. For
instance, while gold, platinum, gallium or indium complexes,
known as soft π-Lewis acids, may encourage the formation of
nonclassical carbocations as intermediates,[1b,3] harder π-Lewis
acids tend to generate vinyl or allenyl carbocations.[ 4 ] The
cycloisomerization of 1,n-enynes, which has been extensively
studied due to the ability of such systems to transform into a
variety of useful cyclic compounds,[5] is triggered by soft π-Lewis
acid activation through nonclassical carbocations (Scheme 1, Eq.
6
]
1).[
As an example, Echavarren et al reported that
7-alkynylcycloheptatriene derivatives behave as 1,6-enynes and
undergo skeletal reorganization when treated with a gold(I)-based
π-acidic catalyst (Eq. 2).[7],[8] The regioisomeric indene products
obtained in such reactions have been explained by the formation
[a]
Dr M. Vayer, Dr C. Bour, Prof. V. Gandon
Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO),
CNRS UMR 8182, Université Paris-Saclay, Bâtiment 420, 91405
Orsay cedex, France.
Scheme 1. Soft and hard activation of 1,6-enynes and 7-
alkynylcycloheptatrienes.
E-mail: christophe.bour@universite-paris-saclay.fr
E-mail: vincent.gandon@universite-paris-saclay.fr
https://www.icmmo.u-psud.fr/fr/equipes/lcm/polycatalyse/
Prof. V. Gandon
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168,
Ecole Polytechnique, Institut Polytechnique de Paris, route de
Saclay, 91128 Palaiseau cedex, France.
However, the difference between soft and hard activation is not
always so pronounced and many factors can influence the
outcome. In fact, the ancillary ligands, the oxidation state of the
metal, the charge and the counterions can modulate the
activity.[12] Moreover, in many cases, the active species is actually
generated in situ from a two-component mixture, each of which
[b]
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
having a potential activity as π-acid (i.e. activation of a gold halide
with a silver salt), so it can be hard to distinguish which of the two
metals is the active one.[ 13 ] Lastly, the use of a π-acid can
generate protons in the reaction mixture, which are also potent
catalysts, as shown above.[14]
and hydroarylation products, a Brønsted acid-catalyzed tandem
hydroarylation/Friedel-Crafts reaction has been developed. A rare
type of skeletal reorganization involving the 1,3-acetonide tether
in the presence of a univalent cationic Ga(I)+ complex leading to
complex polycyclic structures is also described herein.
In order to predict the general π-Lewis acidity pattern of a catalyst,
we designed substrate 1a, containing a 7-alkynylcycloheptatriene
moiety tethered to a phenyl group (Scheme 2).[11a] This compound
is readily synthesized in two steps from dimethyl propargyl
malonate after benzylation and functionalization by tropylium
tetrafluoroborate. Treated with soft π-Lewis acids (Au(I), Pt(II),
Hg(II), Ga(III), In(III), In(I) …), it leads to the regioisomeric indenes
2a and 3a, leaving the Ph group untouched. Treated with harder
π-Lewis acids (Ag(I), Ga(III)+, Cu(II), HX …), the 7-alkynyl
cycloheptatriene moiety transforms into a phenylallene, which is
trapped by the Ph group to deliver the hydroarylation product 4a.
If strong superacids are accidentally released (for instance by
using of AgSbF6 in DCE, which delivers HSbF6),[ 15 ] or used
intentionally (HNTf2), a second hydroarylation takes place to
furnish the tricyclic product 5a.
Results and Discussion
The indene framework can be found in a variety of drug
candidates[16] and of metallocene complexes.[17] Among them,
n-(3-phenylpropyl)-1H-indene derivatives (n = 1, 2, 3) have found
applications in catalyst systems containing
a
bridged
metallocene.[18] Synthetic routes to these aryl-tethered indenes
are still scarce.[19] Two different gold precatalysts were used for
this study: [(JohnPhos)Au(MeCN)][SbF6] (Cond. A) and
a
combination of (Ph3P)AuCl and AgSbF6 (Cond. B). As mentioned
above, when treated by such Au(I) species, the
7-alkynylcycloheptatriene 1a rearranges into the phenyl-tethered
indenes 2a and 3a in good yields (Table 1, entry 1).[7] The best
regioselectivity, in favor of 2a, was obtained under Cond. A. The
same selectivity was observed with other substrates. While the
reaction still worked well with a N-tosyl tether under Cond. A or B
(entry 2), degradation was observed with an oxygen linker (entry
3). The 9,9-fluorenyl tether led only to indene 2d, with a good yield
of 88% under Cond. B (entry 4). The same selectivity was
observed for indene 2e exhibiting a 1,3-acetonide tether (entry 5).
The yields seem more modest in this case, but in fact, 2e is
accompanied by substantial amount of diol 6, which arises from
the hydrolysis of 2e. The substitution of the pendant Ph group did
not influence the reactivity (entries 6-10). In all cases, yields were
good to excellent and a slightly better regioselectivity was
observed when Cond. B were used.
Table 1. Indenes formation from 1a-j.
Scheme 2. Isomerization pathways of the 7-alkynylcycloheptatriene compound
1a (E = CO2Me; LA = Lewis Acid; DCE = 1,2-dichloroethane).
Cond. A
Ratio 2/3
(Yield [%])[a]
Cond. B
Ratio 2/3
(Yield [%])[ a]
Entry
Substrate
Beyond this Lewis acidity test, we saw in compounds of type 1a a
good opportunity to synthesize useful cyclic products from readily
available polyunsaturated substrates. As a special case of 1,6-
enynes with additional unsaturations, 7-alkynylcycloheptatrienes
are indeed fine candidates to increase the molecular complexity
from simple precursors.[7,8] We thus decided to study the scope of
the above reaction by modifying the nature of the tether and by
introducing substituents at the Ph group. In addition to indenes
1
80/20 (87)
60/40 (83)
60/40 (69)
60/40 (65)
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
[b]
[b]
3
4
5
-
-
100/0 (63)
100/0 (88)
100/0 (45)[c]
100/0 (30)[c]
6
7
87/13 (84)
85/15 (86)
95/5 (91)
Scheme 3. Skeletal reorganization of 1k.
After having demonstrated the ability of aryl-tethered
7-alkynylcycloheptatrienes to yield 2-(3-phenylpropyl)-1H-indene
derivatives when treated by a gold catalyst, we then focused on
the hydroarylation reaction. This transformation gives an easy
access to functionalized alkenes or alkanes.[20] As previously
described by Kitagawa[10] and more recently by us,[11a]
7-alkynylcycloheptatrienes are able to rearrange into
phenylallenes. Therefore, in the presence of a suitable catalyst,
the pendant aryl moiety could then promote the hydroarylation of
the allene moiety. After a large screening of various catalysts on
our benchmark substrate 1a (see the Supporting Information),
Cu(OTf)2 proved to be the most efficient one. It provided the
desired hydroarylation product 4a in 96% yield (Table 2, entry 1).
Replacing the gem-diester tether by a N-tosyl group led to a
dramatic decrease of the yield (entry 2). With a 9,9-fluorenyl
tether, 4d was isolated in 40% yield (entry 3). Only
decomposition was observed with an oxygen (entry 4) or a 1,3-
acetonide tether (entry 5). These results highlight once again the
crucial role of the substrate backbone esters in metal-catalyzed
cyclizations.[21] The substitution of the aryl moiety with a methoxy
group gave an almost 1/1 mixture of the para and ortho isomers
4f and 4f’, with E/Z mixture for 4f. A deactivating chlorine atom
instead of a methoxy group led to the para isomer 4g exclusively.
With electron-rich aryl moieties such as dimethoxy, di- or
trimethyl benzene, or with a naphthalene group, the reaction took
place in moderate to very good yields and gave E/Z mixtures, the
E isomer being the major one. Since they are β‑benzylstyrenes,
such compounds are interesting precursors for more complex
structures.[22]
90/10 (65)
8
80/20 (69)
85/15 (56)
9
75/25 (67)
85/15 (69)
80/20 (55)
100/0 (39)
10
[a] Isolated. [b] Degradation. [c] Diol 6 has been isolated in 34% under Cond. A
and 29% under Cond. B.
Substrate 1k, exhibiting a E-styrenyl moiety, was also tested. In
previous work reported by Echavarren, the barbaralane 7,
resulting from the capture of the gold carbene intermediate, was
Table 2. Hydroarylation of 1a-l.
exclusively
obtained
from
1k
when
treated
with
[IPr∙Au(MeCN)][SbF6] at room temperature.[7] Under our
conditions at 80 °C with [(JohnPhos)Au(MeCN)][SbF6] as a
catalyst, barbaralane 7 was found as a minor product (22%
isolated yield at 25 °C and 8% at 80 °C). Instead, a mixture of
indenes 2k and 3k were isolated with a yield of 38% at 25 °C and
49% at 80 °C. (Scheme 3).
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Yield
[%][a]
(E/Z
En
try
Substrate
Product
83
(80/20)
11
ratio)
96
(100/0)
1
[a] Isolated. [b] Decomposition.
Of note, by blocking the hydroarylation by methyl substituents as
in 1m, 1,3-diene 8 deriving from the decumulation of the
intermediate phenylallene was isolated in 55% yield (Scheme 4).
In contrast with our previous work on the [IPr·GaX2][SbF6]
catalyzed cycloisomerization of arenynes, no ipso attack and
methyl shift was observed with a cycloheptatrienyl moiety.[ 23 ]
Isomerisation of allenes into 1,3-dienes has been previously
reported with metal catalysts such as palladium[ 24 ] or gold
complexes,[25] or in presence of Brønsted acids.[26]
23
(100/0)
2
3
4
[b]
-
-
40
(100/0)
[b]
5
6
-
-
Scheme 4. Diene formation from 1m in presence the of Cu(OTf)2 (Eq. 2).
88
During the screening of the reaction conditions for the
hydroarylation reaction described above, compound 9a was
isolated when 5 mol% of triflic acid and toluene as solvent were
used (Table 3, entry 1). This product likely arises from a
bimolecular isomerization/hydroarylation/Friedel-Crafts cascade.
Such transformation, where a cyclization intermediate is trapped
by an aromatic nucleophile, was notably studied in gallium- or
(p=80/2
0; o=
100/0)
67
(100/0)
7
gold-catalyzed enyne, allenyne or diyne rearrangements.[6h],[23]
A
brief optimization of the reaction conditions with anisole as
nucleophile was conducted (Table 3). When anisole was
employed as solvent (which corresponds to about 80 equiv), the
desired product 9b was obtained in mixture with 10, which results
from the direct intermolecular trapping of the allene intermediate
by anisole.[27] Raising the temperature to 110 °C considerably
decreased the formation of 10 (entry 3) and 9b was exclusively
obtained with 72% isolated yield when 3 equivalents of anisole
were used in DCE (entry 4). No diastereoselectivity was observed
for this transformation, all compounds being isolated as a 1/1
mixture.
77
(80/20)
8
38
(90/10)
9
Table 3. Optimization of the reaction condition for the bimolecular
hydroarylation/Friedel-Crafts reaction.
82
(60/40)
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Entry
Ar-H
R
Solvent
T [°C]
80
Ratio
9/10
Yield
[%][a]
1
2
3
4
Toluene
(0.15 M)
Me
-
100/0
27/73
95/5
70[b]
[c]
Anisole
(0.15 M)
OMe
OMe
OMe
-
80
-
[c]
Anisole
(0.15 M)
-
110
110
-
Anisole
DCE
100/0
72
(3 equiv)
[a] Isolated. [b] Some amounts of 5a was also observed in the mixture. [c] Not
determined.
A few other aromatic nucleophiles were tested (Scheme 5).
Electron-rich nucleophiles such as 1-methoxy-2-methylbenzene
and 1,2-dimethoxybenzene furnished the desired products 9c and
9d with 66% and 72% respectively while 1-chloro-2-
methoxybenzene, which is less nucleophilic than the previous
ones, led to 9e with 42% yield. The 3-methoxy substitution of the
aryl part of 1a had no influence on the reactivity and gave a
mixture of the para and ortho isomers 9f and 9f' in 64% yield.
Scheme 5. Scope of the bimolecular hydroarylation/Friedel-Craft alkylation.
As mentioned in the introduction, the cycloheptatrienyl test
allowed us to identify new π-acid catalysts, such as the low-valent
cationic indium(I) complex [In(PhF)2][Al(pftb)4] (pftb
OC(CF3)3).[28] The reactions were less selective with the Ga(I)
analog [Ga(PhF)2][Al(pftb)4],[29],[30] but we found a case where this
rare type of low-valent gallium complex promotes a singular
skeletal reorganization. We used this catalyst to study the
rearrangement of 7-alkynylcycloheptatriene 1e, exhibiting a 2,2-
=
dimethyl-1,3-dioxane tether, and faced
a
very unusual
transformation which was dependent on the nature and loading of
the catalyst (Table 4). While no reaction took place with a 2 mol%
loading (entry 1), the two products 11 and 12 were isolated in 30%
and 42% yield respectively when 1e was treated with 5 mol% of
[Ga(PhF)2][Al(pftb)4] (entry 2). This contrasts sharply with gold
catalysis, which selectively promotes indenes 2e-f (entry 5 of
Table 1). Increasing the catalytic loading to 10 mol% led
exclusively to the polycyclic compound 13 in a modest 50%
isolated yield (entry 3). While the 2,6-dioxabicyclo[2.2.2]octane
moiety (tricyclic ketal) is very common, its ring fusion as in 13,
ascertained by 2D NMR experiments (see the Supporting
Information), has been rarely mentioned.[31] Strikingly, all other
Lewis acids tested failed to furnish any of these products (entries
4-11). Either no reaction or degradation took place.
Table 4. Study of various Lewis and Brønsted acids for the skeletal
reorganization of 1e.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Entry
Cat.
x [mol%]
Ratio
Yield
11/12/13
11/12/13
[%][a]
[b]
1
[Ga(PhF)2][Al(pftb)4]
[Ga(PhF)2][Al(pftb)4]
[Ga(PhF)2][Al(pftb)4]
[In(PhF)2][Al(pftb)4]
Ga2Cl4
2
5
10
5
5
5
5
5
5
5
5
-
-
2
40/60/0
30/42/0
Scheme 6. Postulated mechanism for the formation of 11.
3
0/0/100
0/0/50
[b]
4
-
-
-
-
-
-
-
-
-
For the formation of 12 and 13, compound 1e could first undergo
an acid-catalyzed deprotection of the acetal to form diol D and
acetone (Scheme 7). The 7-alkynylcycloheptatriene moiety then
rearranges into the corresponding phenylallene E. One oxygen
atom of the diol triggers a 6-endo-dig cyclization onto the allene
to furnish the tetrahydropyran F and then dihydropyran G after
isomerization of the alkene. Alternatively, a 6-exo-dig cyclization
can lead to G directly. DFT computations performed with
[c]
5
-
[b]
6
IPr·GaCl3/AgSbF6
AgSbF6
-
[c]
7
-
[b]
8
[Ag(DCM)3][Al(pftb)4]
Bi(OTf)3
-
[c]
9
-
+
Ga(PhF)2 as active species and presented in the Supporting
Information strongly support the exo pathway from E to G and the
greater stability of G over F. This enol ether undergoes an aldol-
type condensation with acetone to form oxonium H, which is
rapidly trapped by an alcohol functionality to give I. Finally, 13 is
obtained after acid-catalyzed condensation following pathway (i)
or (ii).
[b]
10
11
PTSA
-
[c]
HNTf2
-
[a] Isolated. [b] No reaction. [c] Degradation.
Although we cannot explain the selectivity of the Ga(I) complex
for this particular reaction compared to the other catalysts tested,
we formulated mechanistic proposals to rationalize the formation
of each product. In an acidic media (X+ = Ga+ or adventitious H+),
cleavage of the acetal can be envisaged to form oxonium A, which
is in equilibrium with the norcaradiene form B (Scheme 6).
Nucleophilic attack of the alkyne to the oxonium, assisted by the
cyclopropyl, leads to C and then to 11 after rearomatization and
protodemetallation.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Scheme 8. Transformation of 1n and 1o into 14 and 15 in presence of
[Ga(PhF)2][Al(pftb)4].
Conclusion
Through this work, we have shown that the aryl-tethered
7-alkynylcycloheptatriene scaffold can be a useful platform to
access a variety of complex molecules. In the presence of a soft
gold(I) catalyst, indene derivatives have been synthetized via
barbaralyl cation intermediates. Under harder copper(II) catalysis,
they are able to isomerize into phenylallenes, which are trapped
by the pendant aryl group through a hydroarylation step. To go
further, a proton-catalyzed bimolecular Friedel-Crafts alkylation
was combined to the hydroarylation reaction by using an external
aromatic nucleophile. Finally, the specific activation of the 2,2-
dimethyl-1,3-dioxane tether, when treated with a cationic Ga(I)
complex, was demonstrated and exploited to access highly
complex structures.
Experimental Section
General Considerations. Reagents were purchased from commercially
suppliers (Alfa Aesar, Sigma Aldrich or TCI) and used as received, unless
stated otherwise. Solvents were dried by distillation under argon from the
followings: THF (sodium/benzophenone); toluene (sodium); 1,2-DCE
(calcium hydride). Organic extracts were, in general, dried over anhydrous
magnesium sulfate (MgSO4). Reactions in overheated solvent were
performed in 10 mL reaction tubes sealed with a Teflon-coated Rodaviss
stopper and immersed in a pre-heated oil bath when necessary. Reactions
were monitored using thin layer chromatography Merck TLC Silica gel 60
F254. The spots were visualized with ultraviolet light and/or p-anisaldehyde
stain with heat as revealing agent. Flash column chromatography was
performed on CombiFlash System with 40-63 µm silica gel and visualized
by short-wavelength ultraviolet light as well as by p-anisaldehyde stain. 1H
and 13C NMR spectra were recorded on Bruker 250, 300 and 360 MHz
spectrometers at 296 K. 1H NMR chemical shifts are reported in ppm using
residual solvent peak as reference (CHCl3: δ = 7.26 ppm). Data for 1H NMR
are presented as follows: chemical shift δ (ppm), multiplicity (s = singlet, d
= doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz)
and integration; 13C NMR spectra were recorded at 63, 75, 90 MHz using
broadband proton decoupling and chemical shifts are reported in ppm
using residual solvent peaks as reference (CHCl3: δ = 77.16 ppm). Infrared
spectra were recorded on a FTIR spectrometer (Perkin-Elmer spectrum
one) and are reported in cm-1. HRMS was performed on a MicrOTOFq
Bruker spectrometer.
Scheme 7. Proposed mechanism for the formation of 12 and 13.
The ability of the [Ga(PhF)2]+ catalyst to promote the formation of
the putative intermediates G and F was studied by DFT
computations at the M062X/6-311+G(2d,2p)//M062X/6-31G(d,p)
level of theory (see the Supporting Information for details).
Structural modifications were envisioned and two other polycyclic
molecules were synthetized when treating 1n and 1o by 10 mol%
of [Ga(PhF)2][Al(pftb)4] in DCE at 80 °C for 3 h (Scheme 8).
Compounds 14 and 15, bearing a naphthalene and an allyl group
respectively, were obtained in 17% and 20% yield. The low yields
observed for this transformation can be explained by
polymerization side-products detected in the crude 1H NMR. This
observation is not surprising since the intermediates to access the
desired products contain an isobutylene moiety and this specific
gallium(I) complex has been reported to catalyze the
polymerization of isobutylene.[29],[32]
Procedure
for
the
Skeletal
Reorganization
of
7-Alkenylcycloheptatrienes 1a-k (Table 1 and Scheme 3): in air, 1a-k
(1.0 equiv) and [(JohnPhos)Au(MeCN)][SbF6] (3 mol%) or (Ph3P)AuCl
(3 mol%) and AgSbF6 (3 mol%) were charged in a 10 mL tube equipped
with a Teflon-coated magnetic stir bar. Distilled 1,2-DCE (0.2 M) was
added and the tube was sealed. The reaction tube was immersed and
stirred in a preheated oil bath at 80 °C during 20 h. The reaction mixture
was filtered through a pad of celite (thoroughly rinsed with Et2O) and
concentrated under reduced pressure. Purification by FC (12 g of SiO2,
Cy/EA: 100/0 to 95/5) afforded the corresponding product.
Procedure for the Hydroarylation of 7-Alkenylcycloheptatrienes 1a-m
(Table 2 and Scheme 4): in air, 1a-m (1.0 equiv) and Cu(OTf)2 (5 mol%)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
were charged in a 10 mL tube equipped with a Teflon-coated magnetic stir
bar. Distilled 1,2-DCE (0.15 M) was added and the tube was sealed. The
reaction tube was immersed and stirred in a preheated oil bath at 80 °C
during 20 h. The reaction mixture was filtered through a pad of celite
(thoroughly rinsed with Et2O) and concentrated under reduced pressure.
Purification by FC (12 g of SiO2, Cy/EA: 100/0 to 95/5) afforded the
corresponding product.
Procedure for the Skeletal Reorganization of 1e (Table 4): in a glove
box, 1e (1.0 equiv), the catalyst (2-10 mol%) and degassed 1,2-DCE (0.15
M) were charged in a 10 mL tube equipped with a Teflon-coated magnetic
stir bar. The tube was sealed, taken out of the glove box, immersed and
stirred in a preheated oil bath at 80 °C during 3 h. The reaction mixture
was filtered through a pad of celite (thoroughly rinsed with Et2O) and
concentrated under reduced pressure. Purification by FC (12 g of SiO2,
Cy/EA: 100/0 to 95/5) afforded the corresponding product.
Procedure for the Bimolecular Hydroarylation/Friedel-Crafts
Reaction of 1a (Table 3): in air, 1a (30 mg, 0.09 mmol, 1.0 equiv), Ar-H (3
equiv or 0.15 M) and distilled solvent (0 or 0.15 M) were charged in a 10
mL tube equipped with a Teflon-coated magnetic stir bar. HOTf (5 mol%)
was added and the tube was sealed. The reaction tube was immersed and
stirred in a preheated oil bath at 80-110 °C during 15 h. The reaction
mixture was filtered through a pad of celite (thoroughly rinsed with Et2O)
and concentrated under reduced pressure. Purification by FC (12 g of SiO2,
Cy/EA: 100/0 to 95/5) afforded the desired compound as mixture of
diastereoisomers (1/1).
Procedure for the Skeletal Reorganization of 1n-o (Scheme 8): in a
glove box, 1n-o (1.0 equiv), [Ga(PhF)2][Al(pftb)4] (10 mol%) and degassed
1,2-DCE (0.15 M) were charged in a 10 mL tube equipped with a Teflon-
coated magnetic stir bar. The tube was sealed, taken out of the glove box,
immersed and stirred in a preheated oil bath at 80 °C during 3 h. The
reaction mixture was filtered through a pad of celite (thoroughly rinsed with
Et2O) and concentrated under reduced pressure. Purification by FC (12 g
of SiO2, Cy/EA: 100/0 to 95/5) afforded the corresponding product.
Procedure for the Bimolecular Hydroarylation/Friedel-Crafts
Reaction of 1a or 1f (Scheme 5): in air, 1a or 1f (1.0 equiv), Ar-H (3 equiv)
and 1,2-DCE (0.15 M) were charged in a 10 mL tube equipped with a
Teflon-coated magnetic stir bar. HOTf (5 mol%) was added and the tube
was sealed. The reaction tube was immersed and stirred in a preheated
oil bath at 110 °C during 15 h. The reaction mixture was filtered through a
pad of celite (thoroughly rinsed with Et2O) and concentrated under reduced
pressure. Purification by FC (12 g of SiO2, Cy/EA: 100/0 to 95/5) afforded
the desired compound as mixture of diastereoisomers (1/1).
Acknowledgements
We are grateful to the MESRI (PhD grant for MV), CNRS,
Université Paris-Saclay and Agence Nationale de la Recherche
(ANR-18-CE07-0033-01 (HICAT)). We are thankful to the
Umicore Company for a generous gift of metal complexes.
Keywords: Alkynes • Allenes • Cycloisomerization •
Hydroarylation • Friedel-Crafts • Rearrangements •
[1]
[2]
a) Y. Yamamoto, J. Org. Chem., 2007, 72, 7817-7831; b) A. Fürstner, P.
W. Davies, Angew. Chem. Int. Ed., 2007, 46, 3410-3449; c) A. S. K.
Hashmi, Chem. Rev., 2007, 107, 3180-3211.
Escribano-Cuesta, N. Huguet, C. Obradors, Org. React., 2017, 92, 1; l)
X. Zhao, M. Rudolph, A. S. K. Hashmi, Chem. Commun., 2019, 55,
12127-12135.
a) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed., 2004, 43, 46-58;
b) W. R. J. D. Galloway, A. Isidro-Llobet, D. R. Spring, Nat. Commun.,
2010, 1, 80-92; c) S. Yi, B. V. Varun, Y. Choi, S. B. Park, Front. Chem.,
2018, 6, article 507; d) Y. Gu, C. Tan, J. Gong, Z. Yang, Synlett, 2018;
29, 1552-1571.
[7]
[8]
P. R. McGonigal, C. de León, Y. Wang, A. Homs, C.R. Solorio-Alvarado,
A.M. Echavarren, Angew. Chem. Int. Ed., 2012, 51, 13093-13096.
For other applications of 7-alkynylcycloheptatrienes, see: a) Trevor S.
Abram, William E. Watts, J. Organometal. Chem. 1976, 105, C16-C18;
b) S. Ferrer, A. M. Echavarren, Angew. Chem. Int. Ed., 2016, 55, 11178-
11182; c) A. N. Bismillah, J. Sturala, B. M. Chapin, D. S. Yufit, P.
Hodgkinson, P. R. McGonigal, Chem. Sci., 2018, 9, 8631-8636; d) S.
Ferrer, A. M. Echavarren, Synthesis, 2019, 51, 1037-1048; e) A. N.
Bismillah, B. M. Chapin, B. A. Hussein, P. R. McGonigal, Chem. Sci.,
2020, 11, 324-332.
[3]
a) D. J. Gorin, F. D. Toste, Nature, 2007, 446, 395-403; b) A. Leyva-
Pérez, A. Corma, Angew. Chem. Int. Ed., 2012, 51, 614-635; c) M.
Pernpointner, A. S. K. Hashmi, J. Chem. Theory Comput., 2009, 5, 2717-
2725; d) L. Nunes dos Santos Comprido, J. E. M. N. Klein, G. Knizia, J.
Kästner, A. S. K. Hashmi, Angew. Chem. Int. Ed., 2015, 54, 10336-
10340; e) Y. Wang, M. E. Muratore, A. M. Echavarren, Chem. Eur. J.
2015, 21, 7332-7339.
[9]
a) J. B. Lambert, Tetrahedron Lett., 1963, 4, 1901-1906; b) P. Ahlberg,
J. B. Grutzner D. L. Harris, S. Winstein, J. Am. Chem. Soc., 1970, 92,
3478-3480; c) P. Ahlberg, D. L. Harris, S. Winstein, J. Am. Chem. Soc.,
1970, 92, 4454-4456.
[4]
[5]
a) M. Niggemann, N. Bisek, Chem. Eur. J., 2010, 16, 11246-11249; b) G.
Lemière, B. Cacciuttolo, E. Belhassen, E. Duñach, Org. Lett., 2012, 14,
2750-2753.
[10] a) T. Kitagawa, J. Kamada, S. Minegishi, K. Takeuchi, Org. Lett., 2000,
2, 3011-3013; b) S. Minegishi, J. Kamada, K. Takeuchi, K. Komatsu, T.
Kitagawa, Eur. J. Org. Chem., 2003, 3497-3504.
a) V. Michelet, P. Y. Toullec, J.-P. Genêt, Angew. Chem. Int. Ed., 2008,
47, 4268-4315; b) E. Jiménez-Nꢀꢁez, A. M. Echavarren, Chem. Rev.,
2008, 108, 3326-3350; c) S. I. Lee, N. Chatani, Chem. Commun., 2009,
371-384.
[11] a) M. Vayer, R. Guillot, C. Bour V. Gandon, Chem. Eur. J., 2017, 23,
13901-13905; b) J. Tian, Y. Chen, M. Vayer, A. Djurovic, R. Guillot, R.
Guermazi, S. Dagorne, C. Bour, V. Gandon, Chem. Eur. J. 2020,
10.1002/chem.202001376.
[6]
a) Z. Li, C. Brouwer, C. He, Chem. Rev., 2008, 108, 3239-3265; b) A.
Fürstner, Chem. Soc. Rev., 2009, 38, 3208-3221; c) N. Shapiro, F. D.
Toste, Synlett, 2010, 675-691; d) S. P. Nolan, Acc. Chem. Res., 2011,
44, 91-100; e) C. Obradors, A. M. Echavarren, Acc. Chem. Res., 2014,
47, 902-912; f) L. Fensterbank, M. Malacria, Acc. Chem. Res., 2014, 47,
953-965; g) R. Dorel, A. M. Echavarren, Chem. Rev., 2015, 115, 9028-
9072; h) R. Dorel, A. M. Echavarren, J. Org. Chem., 2015, 80, 7321-
7332; i) Y. Wang, M. E. Muratore, A. M. Echavarren, Chem. Eur. J., 2015,
21, 7332-7339; j) D. Pflästerer, A. S. K. Hashmi, Chem. Soc. Rev., 2016,
45, 1331-1367; k) A. M. Echavarren, M. Muratore; V. López-Carrillo, A.
[12] a) M. Jia, M. Bandini, ACS Catal., 2015, 5, 1638-1652; b) F. Jaroschik,
A. Simonneau, G. Lemière, K. Cariou, N. Agenet, H. Amouri, C. Aubert,
J.-P. Goddard, D. Lesage, M. Malacria, Y. Gimbert, V. Gandon, L.
Fensterbank, ACS Catal., 2016, 6, 5146-5160.
[13] a) G. Fang, X. Bi, Chem. Soc. Rev., 2015, 44, 8124-8173; b) Y. Yang, P.
Antoni, M. Zimmer, K. Sekine, F. F. Mulks, L. Hu, L. Zhang, M. Rudolph,
F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed., 2019, 58, 5129-
5133; c) S. Dabral, B. Bayarmagnai, M. Hermsen, J. Schießl, V. Mormul,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
[22] a) W.-F. Chen, H.-Y. Lin, S. A. Dai, Org. Lett., 2004, 6, 2341-2343; b) X.
Cai, A. Keshavarz, J. D. Omaque, B. J. Stokes, Org. Lett., 2017, 19,
2626-2629; c) X. Cai, A. Tohti, C. Ramirez, H. Harb, J. C. Fettinger, H.
P. Hratchian, B. J. Stokes, Org. Lett., 2019, 21, 1574-1577.
A. S. K. Hashmi, T. Schaub, Org. Lett., 2019, 21, 1422-1425; d) F. Chen,
A. S. K. Hashmi, Org. Lett., 2016, 18, 2880-2882; e) A. A. Niklas, F.
Heinrich, S. R. Kohl, M. Hokamp, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Adv. Synth. Catal., 2019, 361, 5605-5615; f) A. Stephen K.
Hashmi, in Silver in Organic Chemistry (Ed. M. Harmata), John Wiley and
Sons, Inc., Hoboken, 2010, 357-379; Chapter 12 "A Critical Comparison:
Copper, Silver and Gold".
[23] B. Michelet, S. Tang, G. Thiery, J. Monot, H. Li, R. Guillot, C. Bour, V.
Gandon, Org. Chem. Front., 2016, 3, 1603-1613.
[24] a) M. Al-Masum,Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 3809-
3810; b) S. Pascual, C. Bour, P. de Mendoza, A. M. Echavarren, Beilstein
J. Org. Chem., 2011, 7, 1520-1525; c) Y. Al-Jawaheri, M. Turner, M. C.
Kimber, Synthesis, 2018, 50, 2329-2336.
[14] a) T. C. Wabnitz, J.-Q. Yu, J. B. Spencer, Chem. Eur. J., 2004, 10, 484-
493; b) D. Munz, M. Webster-Gardiner, R. Fu, T. Strassner, W. A.
Goddard III, T. B. Gunnoe, ACS Catal., 2015, 5, 769-775; c) I. Šolic´, H.
X. Lin, R. W. Bates, Tetrahedron Lett., 2018, 59, 4434-4436.
[15] For the formation of HSbF6, see: C. Bour, R. Guillot, V. Gandon, Chem.
Eur. J., 2015, 21, 6066-6069.
[25] C.-M. Ting, Y.-L. Hsu, R.-S. Liu, Chem. Commun., 2012, 48, 6577-6579.
[26] a) T. L. Jacobs, R. N. Johnson, J. Am. Chem. Soc., 1960, 82, 6397-6404;
b) R. Sanz, D. Miguel, A. Martínez, M. Gohain, P. García-García, M. A.
Fernández-Rodríguez, E. Álvarez, F. Rodríguez, Eur. J. Org. Chem.,
2010, 7027-7039.
[16] a) Y. Ishiguro, K. Okamoto, F. Ojima, Y. Sonoda, Chem. Lett., 1993,
1139-1140; b) C. H. Senanayake, F. E. Roberts, L. M. DiMichele, K. M.
Ryan, J. Liu, L. E. Fredenburgh, B. S. Foster, A. W. Douglas, R. D.
Larsen, T. R. Verhoeven, P. J. Reider, Tetrahedron Lett., 1995, 36, 3993-
3996; c) H. Gao, J. A. Katzenellenbogen, R. Garg, C. Hansch, Chem.
Rev., 1999, 99, 723-744; d) J. L. Wood, B. G. Pujanauski, R. Sarpong,
Org. Lett., 2009, 11, 3128-3131.
[27] The intermolecular hydroarylation competes under these specific
conditions (anisole as solvent, corresponding to about 80 equiv) with the
intramolecular hydroarylation which is normally observed under these
reaction conditions (see Table 2, entry 14 in Ref 11a).
[28] a) S. Welsch, M. Bodensteiner, M. Dušek, M. Sierka, M. Scheer, Chem.
Eur. J., 2010, 16, 13041-13045; b) A. Higelin, U. Sachs, S. Keller, I.
Krossing, Chem. Eur. J., 2012, 18, 10029-10034.
[17] a) T. E. Ready, J. C. W. Chien, M. D. Rausch, J. Organomet. Chem.,
1996, 519, 21-28; b) H. G. Alt, A. Köppl, Chem. Rev., 2000, 100, 1205-
1221; c) J. Schellenberg, Prog. Polym. Sci. 2009, 34, 688-718.
[18] R. M.; Buck, Q. Yang, A. P. Masino, C. E. Wittner, PCT Int. Appl.,
2013151863; PCT Int. Appl., 2012048067; PCT Int. Appl., 2013151863.
[19] a) H. Someya, H. Yorimitsu, K. Oshima, Tetrahedron, 2010, 66, 5993-
5999; b) S. Ni, J. Franzén, Chem. Commun., 2018, 54, 12982-12985; c)
J. Duan, Y.-F. Du, X. Pang, X.-Z. Shu, Chem. Sci., 2019, 10, 8706-8712.
[20] T. de Haro, C. Nevado, Comprehensive Organic Synthesis II, 2014, 5,
1621.
[29] M. R. Lichtenthaler, A. Higelin, A. Kraft, S. Hughes,A. Steffani, D. A.
Plattner, J. M. Slattery, I. Krossing, Organometallics, 2013, 32, 6725-
6735.
[30] Z. Li, G. Thiery, M. R. Lichtenthaler, R. Guillot, I. Krossing, V. Gandon,
C. Bour, Adv. Synth. Catal., 2018, 360, 544-549.
[31] S. L Schreiber, B. Hulin, Tetrahedron Lett., 1986, 27, 4561-4564.
[32] M. R. Lichtenthaler, S. Maurer, R. J. Mangan, F. Stahl, F. Mönkemeyer,
J. Hamann, I. Krossing, Chem. Eur. J., 2015, 21, 157-165.
[21] a) M. E. Jung, G. Piizzi, Chem. Rev., 2005, 105, 1735-1766; b) B.
Michelet, G. Thiery, C. Bour and V. Gandon, J. Org. Chem., 2015, 80,
10925-10938.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000623
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
The reactivity of 7-alkynycycloheptatrienes tethered to an aryl group under π-acid catalysis has been studied. A variety of useful cyclic
products were synthesized via Au(I)-catalyzed skeletal reorganization, Cu(II)-catalyzed hydroarylation or Brønsted acid-catalyzed
tandem hydroarylation/Friedel-Crafts reaction. We also report a rare type of skeletal reorganization involving the 1,3-acetonide tether
in the presence of a univalent cationic Ga(I)+ complex.
Institute and/or researcher Twitter usernames: @MarieVayer, @CBourUPSaclay, @vincent_gandon
This article is protected by copyright. All rights reserved.