Bimolecular vinylation of arenes by vinyl cations

Article abstract of DOI:10.1039/d0cc02300k

Styrene derivatives can be easily synthesized from vinyl triflates and arenes under mild reaction conditions, using [Li][Al(OC(CF3)3)4] as a catalyst and LiHMDS as a base. This transformation is likely to involve a vinyl cation intermediate as an electrophile, which is corroborated by DFT calculations, deuterium-labeling and other control experiments. The use of an inert weakly coordinating anion is a decisive factor in this bimolecular vinylation process. This journal is

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Bimolecular Vinylation of Arenes by Vinyl Cations
Zhilong Li,a Vincent Gandon,*a,b and Christophe Bour*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Styrene derivatives can be easily synthesized from vinyl triflates diazo ketones with Lewis acids. This approach allows the
and arenes under mild reaction conditions, using [Li][Al(OC(CF3)3)4] formation of tricyclic 1-indenones after intramolecular
as a catalyst and LiHMDS as a base. This transformation is likely to vinylation of the aryl rings by the vinyl cation.3 As for
involve a vinyl cation intermediate as electrophile, which is intermolecular reactions, the heterolytic solvolysis of vinyl
corroborated by DFT calculations, deuterium-labeling and other sulfonates10 route has been investigated. Stang and Anderson
control experiments. The use of an inert weakly coordinating anion reported that tetrasubstituted vinyl triflates or trisubstituted
is a decisive factor in this bimolecular vinylation process.
cyclic vinyl triflates are arylated when heated at high
temperature in an aromatic solvent (Scheme 1).11
The more than 140 years old Friedel-Crafts reaction remains
one the most frequently used method for the functionalization
of arenes.1,2 Although carbon based electrophiles have been
widely used, the direct vinylation of aromatic rings remains
difficult to achieve. In 2018, Fang and Brewer attributed the lack
of examples of vinylation of arenes to the difficulty to prepare
vinyl cations compared to classical tricoordinated carbonium
ions.3 Mayr et al stated that vinyl cations are sluggish
electrophiles due to the high intrinsic barrier for sp2
↔sp
rehybridization, hence a slow solvolysis of the precursor and a
high energy level of such intermediates.4 However, the carbene-
like reactivity of vinyl cations, revealed by concerted CH-
insertion processes,5 has been highlighted.6 One way to
generate vinyl cations is by adding electrophiles to alkynes7 but
their trapping by arenes suffers from regioselectivity issues and
the styrene products can be prone to polymerization under the
strongly acidic conditions used (TFA, HNTf2, TfOH, hard Lewis
acids, etc).8 Milder reaction conditions have been developed
using soft transition metal complexes as catalysts, but apart
from intramolecular reactions or reactions in which the two
alkyne carbons are functionalized, regioselectivity and
oligomerization processes remain an issue.9,5b Another way to
generate vinyl carbocations is by decomposing -hydroxy--
a.Institut de Chimie Moléculaire et des Matériaux d
’Orsay, CNRS UMR 8182,
Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex (France). Email:
vincent.gandon@universite-paris-saclay.fr; christophe.bour@universite-paris-
saclay.fr
Scheme 1. Vinylation of arenes using vinyl triflates (RF = C(CF3)3)
.
b. Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique,
Institut Polytechnique de Paris, route de Saclay, 91128 Palaiseau cedex, France
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Nelson et al showed that a similar reaction could be realized used as solvent (entries 1 and 2). LiHMDS was used as a base to
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DOI: 10.1039/D0CC02300K
under milder conditions using a silylium ion associated with a possibly encourage the deprotonation step of the Friedel-Crafts
weakly coordinating anion (WCA) to activate the vinyl triflate reaction.16 The joint use of [Ga][Al(OC(CF3)3)4] (5 mol%) and
and promote the formation of a vinyl carbocation.5d However, LiHMDS (1.1 equiv) delivered the desired product 2a in 58%
the double bond is reduced by the silane to provide an alkyl- yield based on 1H NMR (entry 3). In the absence of catalyst, no
arene. Our interest for Lewis acid catalyzed Friedel-Crafts reaction took place (entry 4). Changing the Ga(I) catalyst for
reaction12 led us to investigate a way to use vinyl triflates as GaCl3 shut down the reactivity (entry 5). With
vinylation agents under mild conditions. Recently, we reported [In][Al(OC(CF3)3)4], 2a was formed in 60% yield (entry 6). We
that univalent gallium and indium salts of the WCA also tested the lithium salt [Li][Al(OC(CF3)3)4] which proved
[Al(OC(CF3)3)4]- are excellent catalysts for the intramolecular ineffective alone (entry 7), but efficient when use together with
vinylation of arenes using alkynes or allenes.13 [Al(OC(CF3)3)4]- LiHMDS (entry 8). This stable complex can be readily prepared
presents several important advantages compared to other on a large scale from LiAlH4 and HO(C(CF3)3)4.17 Lowering the
WCAs, such as solubility, chemical stability and inertness.14 We temperature to 30 °C resulted in a much longer reaction time of
thus decided to study the more challenging bimolecular 24 h instead of 1 h (entry 9). Other bases were tested but none,
vinylation of arenes using vinyl triflates and [M][Al(OC(CF3)3)4] including KHMDS, furnished product 2a (entries 10-14). Going
complexes as catalysts. As shown in Scheme 1, our best back to LiHMDS, the simple salt LiBF4 did not promote the
conditions are with [M] = Li (2 mol%), in the presence of LiHMDS reaction (entry 15). The best conditions are shown in entry 16:
as base (1.5 equiv). During the preparation of this manuscript by using [Li][Al(OC(CF3)3)4] at the low loading of 2 mol% and
appeared a pre-print from Nelson et al describing the same LiHMDS (1.5 equiv), an NMR yield of 68% was obtained at 80 °C
transformation, using urea derivatives as catalysts (10 mol%) in 2 h.
and also LiHMDS as base (2-3 equiv).15 We report herein our The scope of this lithium-catalyzed vinylation was then explored
own findings.
(Scheme 2). Two different experimental conditions were
As mentioned above, our investigation began with the use of developed: either using the arene directly as solvent (benzene,
[Ga][Al(OC(CF3)3)4] and [In][Al(OC(CF3)3)4] (Table 1). Both toluene and mesitylene), or using pentane as solvent. In the
proved unable to promote the coupling of dec-1-en-2-yl latter case, 2 equiv of arene were employed. The use of pentane
trifluoromethanesulfonate 1a at 80 °C with benzene,
allows the reaction to take place at rt instead of 80 °C. With the
arene partner used as solvent, substrates displaying alkyl chains
Table 1. Optimization of the vinylation of benzene using dec-1-en-2-yl
trifluoromethanesulfonate.
were well-tolerated, providing styrenes 2a
Triflates exhibiting cyclohexene, cycloheptene and cyclooctene
could also be coupled to benzene (2d 2g 2h), toluene (2e) or
-c in good yields.
,
,
mesitylene (2f). The reaction did not proceed with a smaller 5-
membered ring (see Unreactive Substrates) The use of 1-
phenylvinyltriflate 1i furnished 1,1-diphenylethylene 2i in 83%
yield. This product was obtained with the same isolated yield of
83% in pentane. Still in pentane as solvent, it was possible to
use 1-phenylvinyltriflates displaying electron-withdrawing p-F
[M] or other
cat.
[Ga]
[In]
Yield
(%)a
Entry
Base
Temp
time
(
1j), p-Cl (1k), p-Br (1l) and p-CF3 (1m) groups, as well as the
1
2
-
-
80
80
80
80
80
80
80
80
30
80
80
80
80
80
80
1
1
-
-
electron-donating m-CH3 (1n) group. On the other hand, the p-
NO2 group deactivated the substrate. Arene partners such as
1,4-dichloro- or 1,4-dibromobenzene, and 1-(phenylsulfonyl)-
1H-indole could not be used, but electron-rich mesitylene, p-
xylene, 1,4-dimethoxy- and 1,3,5-trimethoxybenzene proved
3
[Ga]
-
LiHMDS
LiHMDS
LiHMDS
LiHMDS
-
1
58
-
4
24
24
1
5
GaCl3
[In]
-
6
60
-
perfectly compatible (2o-r). Of note, 2,2-diphenylvinyltriflate 1s
7
[Li]
24
1
transformed into diphenylacetylene under our reaction
conditions. This is likely the result of a base promoted Fritsch-
Buttenberg-Wiechell rearrangement involving a vinyl carbene.18
Triflate elimination was also observed using the peculiar
8
[Li]
LiHMDS
LiHMDS
KHMDS
K2CO3
64
60
-
9
[Li]
24
1
10
11
12
13
14
15
[Li]
[Li]
1
-
conjugated substrate 1t
.
[Li]
DTBPb
1
-
Although this alkyne formation is not surprising in this case, it
raised the question of a hydroarylation pathway to explain the
reaction products. One could indeed imagine that a coupling
product such as 2b could be obtained after base-promoted
triflate elimination to give 1-octyne, followed by Li+-catalyzed
hydroarylation (Scheme 3, eq (1)). However, 1-octyne could not
be converted into 2b with or without LiHMDS (eq (2)). The use
of C6D6 under the two experimental conditions (eqs (3) and (4))
led to the expected styrenes 2a-d5 and 2i-d5, yet accompanied
[Li]
Et3N
1
-
[Li]
DMAP
LiHMDS
LiHMDS
(1.5 equiv)c
1
-
LiBF4
24
-
16
[Li] (2 mol%)
80
2
68
a NMR yield using 1,3,5-trimethoxybenzene as internal standard (added after
workup). A dash means no reaction. b 2,6-di-tert-butylpyridine. c 0.2 M. RF =
C(CF3)3.
2 | J. Name., 2012, 00, 1-3
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by substantial amounts of products incorporating one C6D5 ring. Finally, base-promoted elimination of H+ or D+
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deuterium at the terminal vinylic position (2a-d6 and 2i-d6). provides the vinylated benzene productsDoOfIt:h10e.1d053a9/nDd0CdC6 0se23r0ie0sK.
[Li][Al(ORF)4] (2 mol%)
These structures cannot be explained by a standard Friedel-
hydroarylation?
LiHMDS (1.5 equiv)
C6H6, 80 °C, 1 h
Crafts mechanism.
1b
2b
(1)
(2)
(3)
R1
R2
R1
R3
R2
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
R3
OTf
R
(0.2 M)
ArH: as solvent, 80 °C
2b unobserved
or 2 equiv in pentane (0.1 M), 1 h, rt
C6H6, 80 °C, 1 h
ArH as solvent, 1-2 h, 80 oC:a
H
D
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
Me
Cl
R
C8H17
C8H17
1a
+
2 : 1
Ph
d5
d5
C6D6, 80 °C, 1 h
2c, 2 h, 58%b
2d, 2 h, 63%
2e, 2 h, 73%
o:m:p = 3:2:1
2a, R = -C H17, 1 h, 63%
n
8
2a-d5
2a-d6
2b, R = n-C6H13, 1 h, 62%
H
D
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
Ph
(4)
( )n
+
1i
+
C6D6
d5
d5
pentane, rt, 1 h
(2 equiv)
2g (n = 1), 2 h, 82%
2h (n = 2), 1 h, 64%b
2f, 6 h, 55%b
2i, 83% (0.5 h)
2i-d5
2i-d6
2 : 1
Pentane, 1 h, rt:a
2i, R = H, 83%
Scheme 3. Control experiments (RF = C(CF3)3)
.
2j, R = F, 68%
2k, R = Cl, 68%
2l, R = Br, 69%
CF3
R
2m, 58%
2n, 41%
OMe
OMe
OMe
MeO
OMe
2o, 63%
2p, 72%
2q, 65%
2r, 55%
Unreactive substrates:
X
OTf
OTf
N
SO2Ph
O2N
X
Side Reactions:
X = Cl, Br
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
OTf
Ph
Ph
Ph
Ph
C6H6, 80 °C, 1 h
Ph
Ph
71%
Scheme 4. Proposed mechanism (R = Ph; RF = C(CF3)3)
.
1s
[Li][Al(ORF)4] (2 mol%)
LiHMDS (1.5 equiv)
O
OTf
O
A KIE experiment was conducted using C6H6 and C6D6 but the
kH/kD was 1.0. DFT calculations were performed at the
OEt
3 (75%)
OEt
C6H6, 80 °C, 1 h
C6H11
1t

B97XD/6-311+G(d,p)-SMD(pentane) to support the above
proposal (Figure 1). Since conformational sampling of the ion-
pairs is particularly challenging,5d the [Al(OC(CF3)3)4]- anion was
not taken into consideration on the first place. We can yet
ascertain that the ligand exchange between [Al(OC(CF3)3)4]- and
1i to give Int-a/[Al(OC(CF3)3)4]- is an exergonic process (dashed
box, -2.2 kcal/mol). In a naked form, the coordination of Li+ to
1i led to Int-a, located at -17.9 kcal/mol on the energy surface.
Cleavage of the C-O bond requires 21.2 kcal/mol of free energy
of activation to give Int-b, lying at -8.4 kcal/mol. Exchange of
LiOTf by benzene gives Int-c, found at -4.8 kcal/mol. C-C bond
formation is achieved through TScd at the expense of 8.5
kcal/mol. This step is exergonic by 5.4 kcal/mol. Finally, the
[1,3]-H shift corresponds to the highest-lying transition state
TSde, located at 7.5 kcal/mol. As such, the RDS is this final highly
Scheme 2. Scope and limitations (a Isolated yield. b NMR yield using
1,3,5-trimethoxybenzene as internal standard (added after workup)
C(CF3)3).
.
RF =
A proposed catalytic cycle is summarized in Scheme 4. It could
coexist with the standard Friedel-Crafts mechanism, or be the
only effective one as it explains the two types of products (d5
and d6 series). First, lithium coordinates to the OTf moiety to
give
to the vinyl cation
intermediate
carbocation
A
. This promotes the cleavage of the C-O bond and leads to
. Addition of C6D6 gives the Wheland-type
A [1,3]-D shift then gives the tertiary
. This step would seem symmetry-forbidden but it
B
C
.
D
should be largely encouraged by the rearomatization of the
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View Article Oanlninde
Pedro, In Arene Chemistry: Reaction Mechanisms
exergonic process (25.4 kcal/mol from Int-a to TSde). Since it
involves H or D, it does not match the KIE experiment. Thus, the
RDS could correspond to an early slow step. In fact,
[Li][Al(OC(CF3)3)4] is a polymer in the solid state in which each
unit are bound by Li F interaction. Unlike LiHMDS, which is
soluble in benzene or pentane, [Li][Al(OC(CF3)3)4] is not. It is
possible that the reaction takes place at the surface of the salt
or in the interface layer between the solid catalyst and the
solution. Solid-to-solution phase transfer of Li+ could be
promoted by arene Li
Methods for Aromatic Compounds; J. Mortier, Ed.; John Wiley
DOI: 10.1039/D0CC02300K
& Sons, Inc.: Hoboken, NJ, 2016; pp 33-58.
3
4
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
5
Brewer, Chem. Sci., 2017, 8, 6810; d) S. Popov, B. Shao, A. L.
Bagdasarian, T. R. Benton, L. Zou, Z. Yang, K. N. Houk, H. M.
+

 interaction (from benzene or the
Nelson, Science, 2018, 361, 381.
arene reagent used in excess). Such interaction could represent
a competing equilibrium to the binding step of Li+ to 1i and
explain why the reaction requires heating in benzene, in which
6
7
8
M. Niggemann and S. Gao, Angew. Chem. Int. Ed., 2018, 57,
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arene Li+  interaction are maximized, and not in pentane. The

true RDS could actually correspond to the depolymerization of
([Li][Al(OC(CF3)3)4])n or to the arene/triflate ligand exchange,
which we cannot compute. In both case, very little isotope
effect on the reaction rate is expected. To close, it is worthy of
note that a C-H insertion mechanism from Int-c could not be
computed.
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In conclusion, we have developed a mild and efficient method
for the bimolecular vinylation of arenes. This transition metal-
free protocol employs the readily available [Li][Al(OC(CF3)3)4]
complex as catalyst. The use of this robust and inert aluminate
as weakly coordinating anion proved to be a decisive factor.
13 Z. Li, G. Thiery, M. R. Lichtenthaler, R.; Guillot, I. Krossing, V.
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We thank CNRS, UPSaclay, CSC and ANR-18-CE07-0033-01
(HICAT) for financial support. We thank Dr. Solène Miaskiewicz
for useful discussion.
15 A. L. Bagdasarian, S. Popov, B. Wigman, W. Wei, W. Lee and
H.
M.
Nelson,
ChemRxiv
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Conflicts of interest
There are no conflicts to declare.
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