Silylium-Catalyzed Carbon–Carbon Coupling of Alkynylsilanes with (2-Bromo-1-methoxyethyl)arenes: Alternative Approaches

Article abstract of DOI:10.1002/ejoc.201800777

The catalytic activation of alkynylsilanes towards 2-halo-1-alkoxyalkyl arenes gives β-halo-substituted alkynes. It involves the chemoselective substitution of an alkoxide by an alkyne in the presence of a neighboring C(sp³)–Br bond in a cationic C–C bond-forming event. Two complementary protocols to accomplish this new transformation are reported. The outcome of a direct approach based on mixing the precursors with a freshly prepared solution of the active catalytic species (TMSNTf₂) is compared with an alternative based on smooth release of the required silylium ions upon selective activation of the alkyne by gold(I) (JohnPhosAuNTf₂). The two approaches gave satisfactory results to access this otherwise elusive alkynylation process, which furnishes 4-bromo-substituted alkynes and tolerates various functional groups.

Full text of DOI:10.1002/ejoc.201800777

A Journal of
Accepted Article
Title: Silylium-Catalyzed Carbon-Carbon Coupling of Alkynylsilanes
with (2-Bromo-1-methoxyalkyl)arenes: Alternative Approaches
Authors: José Manuel González, Alfredo Ballesteros, and Belén Rubial
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800777
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800777
Supported by

10.1002/ejoc.201800777
European Journal of Organic Chemistry
COMMUNICATION
Silylium-Catalyzed Carbon-Carbon Coupling of Alkynylsilanes
with (2-Bromo-1-methoxyalkyl)arenes: Alternative Approaches
Belén Rubial, Alfredo Ballesteros,* and José M. González*
Dedication ((optional))
Abstract: The catalytic activation of alkynylsilanes towards 2-halo-1-
alkoxyalkyl arenes gives β-halo-substituted alkynes. It involves the
I
I
LDA
chemoselective substitution of an alkoxyde by an alkyne in the
presence of a neighbour C(sp3)-Br bond in a cationic C-C bond-
forming event. Two complementary protocols to accomplish this new
transformation are reported. The outcome of a direct approach
based on mixing the precursors with a freshly prepared solution of
the active catalytic species (TMSNTf2) is compared with an
alternative based on smooth releasing the required silyliun ions upon
selective activation of the alkyne by gold(I) (JohnPhosAuNTf2). The
two approaches gave satisfactory results to access this otherwise
elusive alkynylation process, which furnishes 4-bromo-substituted
alkynes and tolerates various functional groups.
equiv)
(0.4
(1)
(2)
THF,
18 h
40ºC,
Ph
30%,
Ph
OMe
Ph
O
O
:
=
E Z 1:1.3)
(
n
Bu
TiCl
mol%)
12 h
OMe
[Cp2
2] (5
n
BuMgCl
O
THF,
O
-20ºC,
Br
Ph
Ph
70%
H
iPr
Me
Me
N
N
Co
equiv)
(0.15
Me
N
O
N
O
Me
Py
H
I
iPr2NEt
blue LEDs
equiv),
rt, 24 h
(1.5
(3)
(4)
CH3CN,
Ar=
Ar
O
O
Ar
-
H4
4-(MeO)-C6
86%
mol%)
2
Ni(cod) (4
mol%)
Introduction
bathophenantroline
(8
KOt-Bu
equiv)
(1.6
ArB(OH)
2
s
-butanol, 60ºC, 5h
-
The discovery of catalytic carbon-carbon bond-forming reactions
from readily accessible precursors is of ongoing interest.
Moreover, halogen-containing molecules are versatile synthetic
intermediates, so contemporary advances in methodology for
their synthesis is subject of much attention.[1] Cohalogenation
reactions of alkenes provide a flexible entry to β-heteroatom-
substituted organic halides.[2] Due to the electrophilic nature of
these reactions vinyl-substituted arenes are among the most
useful substrates for an efficient regioselective preparation of a
representative array of β-halo-derivatives.
TBSO
TBSO
63%
Ar= 4-F-C6H4
Br
Ar
Br
source"
"silylium
R
Br
Ar
(catalytic)
work)
(this
(5)
R
Ar
OMe Me3Si
Scheme 1. Catalytic reactions from β-halo-substituted benzyl ethers.
The development of new catalytic processes of β-halo
benzyl ethers is desirable to strength their merit as synthetic
building-blocks, since they are available in just one-step from
simple reagents (alcohols, styrenes and a bromonium donor).
Stoichiometric reactions of the carbon-halogen bond were early
documented.[3] Later, catalytic transformations were developed
and the known processes are now collected in Scheme 1. Thus,
the cyclization of O-propargylated substrates in the presence of
LDA gives hetero- or carbocyclic products featuring a halogen-
shift (eq 1).[4] Furthermore, the formation of (1-methoxyoctane-
1,3-diyl)dibenzene (eq 2) was noticed in the alkylation of 2-
bromo-1-methoxyethyl)benzene with alkyl halides catalyzed by
Cp2TiCl2,[5] suggesting that styrene is released and incorporated
into the catalytic cycle.[5b] Photocatalytic radical cyclizations (eq
4) giving Heck-like products,[6] and nickel-catalyzed Suzuki
cross-coupling with boronic acids (eq 5).[7] have been disclosed.
Herein, a silylium-based catalytic approach to accomplish
cross-coupling reactions of trialkylsilyl acetylene derivatives with
(2-bromo-1-methoxyalkyl)arenes is presented (eq 5, Scheme 1).
Results and Discussion
Metal-catalyzed carbon(sp)-carbon(sp3) cross-coupling
reactions are relevant to elaborate alkynes.[8] The transition
metal-catalyzed C(sp)-C(sp3) cross-coupling turns elusive
for electrophiles containing a vicinal halogen-carbon(sp3)
bond.[9] In this context, cationic chemistry[10,11] could be
helpul to access complementary products. Thus, a catalytic
C-C bond-forming process from vic-halohydrines preserving
unaltered the C(sp3)-halogen bond would be a timely
advance in the field.
We decided to broach this possibility from (2-bromo-1-
alkoxyalkyl)arenes following the strategy outlined in
Scheme 2, which relies on the ability of a silicon-based
Lewis acid[12] to activate the sacrificial alkoxy group in
Dr. B. Rubial, Prof. Dr. A. Ballesteros, Prof. Dr. José M. González
Departamento de Química Orgánica e Inorgánica and Instituto
Universitario de Química Organometálica “Enrique Moles”
Universidad de Oviedo
C/ Julián Clavería 8, Oviedo 33006, Spain
E-mail: jmgd@uniovi.es
substrate
1. Its chemoselective activation would lead to I.
Next, the benzylic nature of the leaving group would favor
13]
the formation of the reactive carbocation II [
.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201800777
European Journal of Organic Chemistry
COMMUNICATION
Me
3SiX
Ar
Ar
catalytic
(
)
R
R
SiMe3
Br
-
MeO
MeOSiMe3
Br
Table 1. Evaluation and identification of suitable reaction conditions.
1
2
3
Me
Ar
3SiX
Ph
Ar
Br
Ph
catalyst mol%)
(5
Ar
2
Br
Ph
SiMe3
Br
Br
Br
1,2-dichloroethane
MeO
1a
Me
X
3Si
MeO
Ph
N
2a
M)
3a
(0.5
X
X SiMe3
R
MeOSiMe3
tBu
tBu
iPr
iPr
I
II
III
P
N
=
=
L2 IPr:
L1 JohnPhos:
iPr Pr
i
Scheme 2. Hypothesis behind the proposed alkynylation without bromine lost.
Entry
Catalyst
TMSOTf
T (ºC)/t (h)
Conv.[a]
Yield[b]
A subsequent nucleophilic attack of the alkynylsilane
would afford a -silyl stabilized vinyl cation intermediate III
which would be the responsible for the formation of the
coupling product , at the time of regenerating catalytically
2
1
20/12
20/1
--
--
β
,
[c]
2
TMSNTf2
100
77
55
63
53
--
3
3
HNTf2
20/1.5
competent species. At the onset of this approach is the
potential of silylium ions to catalyze selective organic
reactions.[14-18] Worth noting, there is a scant number of
alkynylations based on the use of alkynylsilanes and
electrophiles featuring oxygen as a leaving group, mostly
limited to sole examples within a context of allylation
reactions of cyclic ethers or diaryl methanol derivatives.[19]
Results from an initial exploratory study are collected in
Table 1. The activity of commercial trimethylsilyl triflate
was first investigated. However, 3a was not formed under
the conditions defined in entry 1. Conversely, the reaction
took place using freshly prepared N-(trimethylsilyl)
bis(trifluoromethanesulfonyl)imide (TMSNTf2) as the
catalyst[20] (entry 2). Simultaneously, different options for in
situ generation of the silylium catalyst were evaluated.
Bis(trifluoromethanesulfonyl)imide (triflimide, entries 3-6)
was assayed.[15] A fast reaction giving 3a was noticed, but
it failed to give full conversion of 1a, even over extended
reaction times. In terms of alternative precursors, the
related reaction of 1a with phenylacetylene 4a gave no
evidence for coupling leading to 3a. Also, the reaction of
phenylacetylene with 2-bromo-1-phenylethanol 5a failed to
give the desired product.
4
HNTf2
20/4
92
5[d]
6[d,e]
7
HNTf2
20/0.7
--
HNTf2
20/1.5
--
--
L1AuNTf2
20/1.5
51
36
30
51
62
50
57
58
71
73
68
30
20
[f]
8
L1AuNTf2
20/4
64
9
AgNTf2
20/3
60
10
11
12
13
14
15
16
17
18
L1AuNTf2
AgNTf2
80/1.5
91
80/0.5
100
100
100
100
100
100
100
79
[c]
TMSNTf2
80/0.05
80/1
HNTf2
L1AuNTf2
L1AuNTf2
100[g]/0.75
120[g]/0.25
120[g]/0.25
120[g]/0.65
120[i]/0.25
[h]
L2AuNTf2
[i]
L1AuNTf2
Attention was focused on in situ release of the required
silylium catalyst by activation of the parent silyl-substituted
alkyne with a Lewis acid.[16-17] In this regard, ZnBr2, PtCl4
and Cu(MeCN)4PF6 failed to convert 1a, irrespectively of
the assayed reaction temperature (20, 80 or 120°C). InCl3
[g]
L1AuNTf2
[a] Conversion calculated by 1H NMR analysis of the crude reaction using
1,3,5-trimethoxybenzene as internal standard. [b] Isolated Yield. [c] Freshly
prepared, for experimental details see ESI. [d] Using phenylacetylene 4a as
nucleophile. [e] For 2-bromo-1-phenylethanol 5a as electrophile. [f] Using 2a
1M. [g] Heating in a microwave oven. [h] Using toluene as solvent. [i] In 1,4-
dioxane as solvent.
activates 1a but it gives only modest yield for 3a (near
20%).[21] AgNTf2 and JohnPhosAuNTf2
[JohnPhos: (2-
[22]
biphenyl)di-tert-butylphosphine] were active precatalyst for
a successful initiation step (entries 7-11), with gold(I) giving
better yield by increasing the reaction temperature up to
80°C. Attempts to improve the yield further modifying the
temperature were made. Using TMSNTf2 at 80ºC (entry
12) the reaction worked nicely but the isolated yield did not
significantly improve that at room temperature (entry 2).
The activity of HNTf2 at this temperature was also tested
(entry 13), 1a was consumed but the yield for 3a was
slightly lower than for gold, even though for the latter full
conversion was not accomplished (entry 10).
At 100°C, the gold-catalyzed process brought about full
conversion and higher yield for 3a (entry 14). Furthermore,
considering the nice functional group tolerance typically
exhibited by gold catalysis and the exquisite level of
chemoselectivity associated with the interaction of alkynes
with gold(I) complexes, it was decided to further optimize
the reaction time for this approach. Additional improvement
was achieved heating at 120°C in a microwave oven
(entries 15-18). Gratifyingly, only 15 minutes were required
for the reaction to afford the coupling product 3a, in 73%
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10.1002/ejoc.201800777
European Journal of Organic Chemistry
COMMUNICATION
isolated yield (entry 15). The fact that σ,π-(alkyne) digold(I)
complexes can be formed and their limited activity[23] might
account for the beneficial effect of heating over the gold-
catalyzed transformations. In fact, 31P-NMR inspection of
the crude reaction mixture corroborated its formation.[21]
Likely, heating might allow to dissociate active mononuclear
species, ensuring the required concentration of the silicon
Lewis acid for a successful coupling. Robust [1,3-bis(2,6-
diisopropylphenyl)imidazolylidene][bis(trifluoromethanesulfo
nyl)imide]gold(I) (IPrAuNTf2,) was tested as precatalyst, but
slightly lower yield was recorded. The role of the solvent
was evaluated (entries 15, 17 and 18). The reaction in
toluene required longer reaction time to consume 1a and
gave lower yield for 3a. The performance of the reaction
conducted in 1,4-dioxane was also inferior.
The conditions outlined in entries 2 and 15, in Table 1,
were selected as the alternatives for studying the scope of
this new catalytic C-C bond-forming event (Scheme 3), and
are termed as method A (entry 2) and method B (entry 15).
The compatibility of different halogens with this process
was proved (3a-c, Scheme 3). Even iodine atoms are
tolerated, but the yield was higher for the case of the
bromohydrin. The influence of the substituents located para
to the reactive benzylic position was analyzed (3d-h
).[24]
Alternatively, using the gold precatalyst, 74% yield of 3f
was isolated. Both methods were convenient to prepare
fluorinated 3h, offering fast and efficient coupling choices;
ortho-substituted precursors are active in this reaction (3i
and 3j). Remarkably, method A was more efficient to
access a 2-naphthyl scaffold present in derivative 3k
.
The alkyne scope is shown in Scheme 4. A silyl-masked
conjugate enyne gave productive formations of 3l for both
TMSNTf2 (Method A) and gold(I) (Method B). Both aryl- and
alkyl alkynes enter this C-C bond-forming process, giving
rise to fast reactions (3m to 3p). Interestingly, remote ester
functionality is compatible with this coupling approach,
though the product was isolated in moderate yield (see 3o).
The reaction was applied to the synthesis of a collection
of small molecules showing moderate functional group
density within interesting topologies. Attention was focused
on a selective and straight synthesis of esters 3q-3t. Only
two electrophilic reactions were required, namely, styrene
bromoalkoxylation and subsequent catalytic coupling of the
assembled
1 with alkynylsilane 2. These examples validate
the merit of this new protocol by selectively preparing an
array of simple functionalities, for which other direct
conceivable disconnections are not of immediate execution.
Besides, allylsilane 6a was a suitable nucleophile for this
Electron-donating groups result in short reaction times and
good isolated yields. The strong electron-withdrawing
carboxylic ester failed to provide full conversion and the
yield was only modest. Less electron-withdrawing halide
substituents still furnish nice synthetic numbers. Usually, in
reaction and nicely furnished 7a
.
Regarding the mechanistic hypothesis in Scheme 2,
additional experimental work was performed to validate
some of the proposed features.
terms of the yield of products 3, method B outperforms the
Br
Br
OMe
results obtained using the preformed silylium catalyst For
3f, the conversion using TMSNTf2 was incomplete. Even
after extended reaction time (overnight) it was in the range
of the 50%. Anyway, it was a clean reaction out of which
the desired product was isolated in 48% yield.
or
A
B
Method
TMS
R
Ar
Ar
-
-
R
or
1a 1h
2 b
3 l t
j
,
:
:
A
B
Method
Method
SiNTf2 mol%),
2Cl)2 20 ºC
(CH
(CH3)3
(5
,
JohnPhosAuNTf2 mol%),
(5
2Cl)2
120
ºC
(CH
(MW)
Br
Br
X
X
X
Ph
or
Ph
A
B
Method
TMS
Ph
:
3m X=
5 min, 65%
B
OMe,
:
3l 30 min, 48%
A
)
(
)
(
Ar
:
3n X= Br, 15 min, 62%
B
Ar
OMe
a-h
3 min, 60%
B
)
(
)
(
Ph
a-k
3
1
2a
SiNTf2 mol%),
Br
Br
X
,
:
:
A
B
Method
Method
2Cl)2 20 ºC
(CH
(CH3)3
(5
(CH
,
JohnPhosAuNTf2 mol%),
(5
2Cl)2
120
ºC
(MW)
Ph
X
Br
:
:
3o X=
5 min, 46%
B
( )
OAc,
F
3p X= Bu, 55 min, 50%
A
)
(
Me
CO2
:
3q 1 71%
B
)
5 min, 51%
B
)
h,
(
(
Br
Br
Ph
Ph
X
:
:
3a: X= Br, 1 55%
h,
A
3d X=
OMe,
1 min, 73%
B
( )
(
),
Me
F
CO2
15 min, 73%
30 min, 40%
B
B
3e X= Me, 5 min, 76%
3f X=
B
(
(
)
)
(
)
:
:
3b X=
Cl,
I,
:
48%
74%
A
B
)
Br,12 h,
( )
3c X= 15 min, 52%
B
F
(
)
3
h,
(
Me
CO2
:
:
:
:
3s 1 37%
h,
B
)
conv)
B
( )
3r 1 61%
B
( )
3g X=
3h X= 30 min, 69%
Me, 6 24%
CO2
h,
(
h,
(48%
A
),
Br
F,
(
Br
1
81%
B
( )
Br
h,
Reaction with:
TMS
6a
Br
Ph
Et
CO2
Et
X
OMe,
3
Ph
Ph
F
:
:
3i X=
1 min, 45%
B
( )
CO2
:
7a
5 min, 50%
B
)
(
:
3j X= Me, 30 min, 77%
A
B
3k 1 87%
A
h,
(
(
(
)
)
(
:
3t 1 71%
h,
B
)
4
64% B at
25ºC)
(
h,
(
min, 85%
5 min, 64%
B
)
10
)
Scheme 4. Coupling products of 1a/1h with alkynylsilanes 2 or allyl silane 6a.
Scheme 3. Coupling of (2-bromo-1-methoxyethyl)arenes with alkyne 2a.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800777
European Journal of Organic Chemistry
COMMUNICATION
Br
Conclusions
OMe
-
Ph
TMS 2a
Catalyst
( ),
Br
In summary, a catalytic C(sp)-C(sp3) coupling reaction
involving a trimethylsilyl-modified derivative of a terminal
alkyne and a benzyl ether having a halogen atom at the β-
Ph
t
T
ClCH2CH2Cl,
(min), (ºC)
Ph
a
1
3a
racemic
S
Ph
mixture
( )
>
ee:
99
%
Catalyst
T
3a
t
(ºC)
20
20
JohnPhosAuNTf2 mol%) 15 120
yield)
(isolated
58%
(min)
15
alkyl position has been settled. Trimethylsilyl bistriflimidate
is an efficient catalyst for this new reaction. Alternatively,
rather than starting from the preformed silylium donor, the
transformation can be executed by carbophilic activation of
silyl-substituted alkynes using a gold precatalyst, which
provides a synthetic toggle to get into Lewis acid catalysis.
It offers a robust entry into a new C-C bond-forming
process that tolerates additional functional groups. Although
the accomplished synthetic efficiency is typically higher
using the latter approach, the former reveals that silylium
ions must be conceptually considered as catalyst to device
new coupling process. The reported transformation is well
suited to afford products with complementary chemo-
selectivity to those arising from metal catalysed cross-
coupling reactions of halohydrins. Work to expand this
chemistry by catalyst improvement and to unveil new
aspects of the scope of the reaction for both, the
electrophile and the nucleophile, are in progress.
TMSNTf2 mol%)
(5
JohnPhosAuNTf2 mol%) 240
45%
72%
64%)
(5
(5
(conversion:
(MW)
Scheme 5. Stereochemical outcome of the catalytic C-C bond forming event.
The involvement of a cationic intermediate as the
ultimate responsible for the C-C bond-forming step is
supported by the racemization noticed for the coupling
reactions of (S)-2-bromo-1-methoxyethyl)benzene (S)-1a
with 2a under the conditions outlined in Scheme 5.[21]
A mechanistic rationale is proposed in Scheme 6. For
the approach following method
B, it is proposed that gold
species trigger the release of the silylium catalyst, although
other role in the coupling could not be firmly ruled out. The
invoked reaction of alkynylsilane with gold(I) is supported
by its carbophilic nature[26] and by precedents for the
regioselective alkynylsilane activation, which operates
under the control of the β
- silicon effect.[26 b)] This accounts
for the formation of a gold acetylide and the release of the
silylium catalyst, which would eventually launch the
coupling. The possibility of a neighbouring assisted ether
ionization by bromine participation was analysed testing the
reaction of a 1:1:1 molar ratio of (1-methoxyethyl)benzene
Acknowledgements
B. R. Would like to acknowledge the Spanish Ministerio de
Educación, Cultura y Deporte for a FPU predoctoral fellowship.
Agencia Estatal de Investigación (AEI), Fondo Europeo de
Desarrollo Regional (FEDER) and Consejería de Economía y
Empleo, Principality of Asturias are acknowledged for financial
aid [Grants CTQ2016-76840-R (AEI/FEDER, UE) and FC-15-
GRUPIN14-013, repectively].
8a, 1a and trimethyl(phenylethynyl)silane 2a catalyzed by
TMSNTf2 (5 mol%).[27] A qualitative estimation of the relative
reactivity’s of 1a and 8a based on the conversions revealed
the former being less reactive, which does not
accommodate neighbour assistance. Then, the alkyne
would trap the carbocation, and the coupling product will
derive from an addition-elimination sequence at the time of
regenerating the catalyst.
Keywords: alkyne • cationic • silicon • cross-coupling • catalysis
[1]
[2]
[3]
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SiMe3
LAu
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R
R
AuL
LAu
LAu
AuL
R
R
SiMe3
Br
AuL
Br
SiMe3
R
SiMe3
MeO
Ar
Ar
R
Me
Me
Br
3Si
Ar
SiMe3
[4]
[5]
O
Br
Ar
O
Me
Me
3Si
a) J. Terao, K. Saito, S. Nii, N. Kambe, N. Sonoda, J. Am. Chem. Soc.
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Scheme 6. Proposed mechanistic rational for the coupling process.
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European Journal of Organic Chemistry
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10.1002/ejoc.201800777
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
The catalytic coupling of the title
compounds affords β-halo-substituted
alkynes. The cationic nature of the C-
C bond-forming event is established
and the actual competence of silylium
species to catalyse this transformation
is proved.
Key Topic*
Belén Rubial, Alfredo Ballesteros*, José
M. González*
Page No. – Page No.
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Silylium-Catalyzed Carbon-Carbon
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Alternative Approaches
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This article is protected by copyright. All rights reserved.