Regio- and Stereoselective N-addition to an Open Bromo Vinyl Cation

Article abstract of DOI:10.1016/j.tetlet.2021.153173

A protocol for the synthesis of thus far inaccessible bromo vinyl triflimides is presented. Our previously reported concept of assisted vinyl cation formation was engaged to achieve both a protonation of relatively electron poor bromo alkynes and a reaction with high regio- and stereoselectivity. To the best of our knowledge, this is the first stereoselective addition of an N-nucleophile to an open β-halovinyl cation.

Full text of DOI:10.1016/j.tetlet.2021.153173

Tetrahedron Letters 74 (2021) 153173
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Tetrahedron Letters
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Regio- and Stereoselective N-addition to an Open Bromo Vinyl Cation
1
1
Marina Chuchmareva , Christina Strauch , Sebastian Schröder, Arndt Collong,
Meike Niggemann
⇑
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol for the synthesis of thus far inaccessible bromo vinyl triflimides is presented. Our previously
reported concept of assisted vinyl cation formation was engaged to achieve both a protonation of rela-
tively electron poor bromo alkynes and a reaction with high regio- and stereoselectivity. To the best of
our knowledge, this is the first stereoselective addition of an N-nucleophile to an open b-halovinyl cation.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 5 March 2021
Revised 27 April 2021
Accepted 6 May 2021
Available online 13 May 2021
Keywords:
Vinyl cation
Haloalkyne
Triflimide
(E)-Alkene
C–N bond formation
Introduction
Another versatile synthon in organic synthesis is the
halogenated olefin. Nevertheless, the stereo- and regioselective
Vinyl triflates are versatile building blocks, most prominently
used as starting materials in transition- metal catalyzed cross-cou-
pling reactions [1–6]. Vinyl triflimides may provide a similarly ver-
satile reactivity, even though not much is known about the
reactivity of these nitrogen-containing analogues [7]. Owing to
our recently developed concept of assisted vinyl cation formation
synthesis of these building blocks is an ongoing challenge.
Although there has been substantial investigation of the elec-
trophilic activation of alkynes by dihalogens or their equivalents
[9–14], the stereoselectivity of such reactions still suffers from
the lack of control over the nature of the transient intermediate,
which heavily depends on the electronics of its substituents. After
initial electrophilic addition of the halogen, the formation of either
a bridged (cyclic) onium ion such as structure III in Scheme 1A or
an open vinyl cation such as structure I is established [15–19].
Bridged onium ions mostly allow for a reliable stereoselective
anti-addition of the nucleophileas in examples B I (a) [20] and B I
(
AVCF), vinyl triflimides have become synthetically accessible for
the first time [8].
The AVCF provides excellent chemo-, regio- and stereoselectiv-
ity via the formation of a supramolecular framework of at least two
2
molecules of water and LiNTf as a readily available bistriflimide
(
TFSI) source [8]. For an efficient AVCF, the transition state of the
(b) [21]. Alternatively, the coordination of a p-electrophilic Lewis
alkyne protonation must be stabilized by the hyperconjugation of
both of the TFSI’s nitrogen lone pairs into the nascent p-orbital of
the vinyl cation. In turn, the second transition state, i.e. that of
the C–N bond formation, must be stabilized by a hydrogen bridge
between the b-proton and the Li-bound hydroxyl group, which
remains from the acidified water molecule that serves as the pro-
ton source in the first step. It is this mutual stabilization of both
transition states, that perfectly positions the N atom for addition
to the vinyl cation (see Scheme 1C) and thus allows for a highly
chemo- and regioselective reaction at an open vinyl cation.
acidic transition metal such as the gold catalyst in example
(c) [22] reliably triggers an anti-addition of the nucleophile. For
open vinyl cations stereochemical outcomes are much less defined
and a selective reaction is more difficult to achieve [15–19,23,24].
As shown in Scheme 1B, (d) the addition of the nucleophile may
occur from either side of the open vinyl cation, solely governed
by steric repulsion. Iodine addition may yield bridged onium ions,
while bromine or chlorine additions tend to yield open b-halovinyl
cations, in line with the bridging ability of the halogen
[15–19,25,26]. The inclination towards a cyclic vs. open intermedi-
ate is further influenced by the substitution pattern of the vinyl
cation, in that the more stabilizing the
the positively charged carbon atom, the less likely a cyclic inter-
mediate becomes [27–31]. Furthermore, both the -and the
a-substituent directly at
⇑
Corresponding author.
E-mail address: niggemann@oc.rwth-aachen.de (M. Niggemann).
Both authors contributed equally.
a
1
https://doi.org/10.1016/j.tetlet.2021.153173
040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
0

M. Chuchmareva, C. Strauch, S. Schröder et al.
Tetrahedron Letters 74 (2021) 153173
Scheme 1. Representative examples of reactions at b-halovinyl cations and reaction design.
b-substituent may also engage in neighbouring group participation
itself and even evolve into a full-blown bridged species such as
structure II in Scheme 1A or the transient silyl-onium species in
example B I (a) [32,33].
Finally, the situation is further complicated by potential low
barrier rearrangements (e.g. to structure IV in Scheme 1A) [15–
19,34], which allow the vinyl cation to quickly equilibrate to its
most stabilized substitution pattern.
2

M. Chuchmareva, C. Strauch, S. Schröder et al.
Tetrahedron Letters 74 (2021) 153173
A second route towards the same b-halovinyl cation intermedi-
ates may be the protonation of a haloalkyne. Even though the
lower electron density in such alkynes makes this process more
difficult, it has been realized in a few cases [35–37]. Although its
origins remain to be elucidated in detail, excellent stereoselectivity
was achieved in some of these reactions [36,37]. Nevertheless, to
the best of our knowledge, a selective syn-addition of an N–H bond,
that is extremely rare even for transition-metal catalyzed reac-
tions, has never been achieved across a haloalkyne [38,22,39].
Hence, to showcase the first selective addition of a nitrogen
nucleophile to an open b-halovinyl cation and at the same time
provide synthetic access to highly interesting bromo vinyl triflim-
ides we designed our reaction according to the following princi-
ples: 1) Aryl substituted bromo alkynes were chosen as
formation had no significant influence on the results (Entries
2–3). Surprisingly, prolonged stirring of the solution before the
addition of acetylene 1a, for establishing an equilibration of the
Li-complex, had no effect on the reaction outcome (not shown).
A first improvement was achieved in the presence of additional
TFSI. In fact, with a combination of an increased amount of LiNTf
(2.0 eq.) and a moderate amount of Bu NPF (0.6 eq.) we were able
2
4
6
to improve the product formationto 49% (Entry 4). Finally, a sol-
vent and temperature screening revealed that a switch to dichlor-
oethane and prolonged heating of the reaction mixture up to 60 °C
leads to a significantly higher yield of 74% (Entry 5). Additional
heating (up to 80 °C) with different amounts of LiNTf did not
2
prove beneficial (Entries 6–8).
With the optimized conditions in hand (Table 1, Entry 5) we
turned our attention to evaluating the reaction scope. Various
bromo alkynes bearing different electronic moieties on the aryl
substituent were subjected to AVCF (Table 2). Gratifyingly, aro-
matic acetylenes with both, electron-withdrawing or electron-
donating aryl groups gave bromo vinyl triflimides 2a–o in moder-
ate to good yields and excellent selectivity. We indeed obtained all
products regioselectively as a single (E)-isomer only.
substrates. Computational analysis suggests that
bromo vinyl cations generally favor open bromo vinyl cations
and rearrangements are disfavored because the -phenyl-b-bromo
vinyl cation is already in its most stable form (see Scheme 1A)
40,41]. 2) AVCF has been used for efficient stereocontrol at the
a-phenyl-b-
a
[
open vinyl cation [8].
The electronic bias on both C atoms of the alkyne is important
for nucleophilic addition of the triflimide anion to the vinyl cation
intermediate. Firstly, the difference in cation stabilizing ability
between the substituents on the two C atoms ensures regioselec-
tive addition at the position adjacent to the aryl substituent
[15–19]. Alkynes with moderately electron-withdrawing aryl sub-
stituents in the para-position gave triflimides 2f,g,l in good yields
(54–69%) since their vinyl cation intermediates are still stabilized
enough. However, alkynes bearing stronger electron-withdrawing
groups, such as the trifluoromethyl group in 1h, show only moder-
ate triflimide yields (18%). The strong electron-withdrawing effect
Results and discussion
2
Given the importance of the self-assembly of a Li-TFSI-H O
supramolecular framework from LiNTf and adventitious water
2
for an efficient assisted vinyl cation formation, we started our
investigation by applying our previous, extensively optimized
reaction conditions [8]. In a first attempt we were able to obtain
only 21% of 2a (determined via 1H NMR analysis) (Table 1, Entry
1
). This is likely due to the electron-withdrawing effect of the
bromo substituent in 1a, making the protonation of the acetylene
significantly more challenging. Increasing the amount of the
of the trifluoromethyl substituent destabilizes the
a-aryl-b-halovi-
4 6 2
Bu NPF additive, which aids LiNTf solubilization and complex
nyl cation [27–31], thus impeding the protonation step. Notably,
Table 1
Optimization of the reaction conditions.
Entrya
X
Y
T [°C]
t (h)
Yield (%)b
1
2
3
1.5
1.5
1.5
2.0
2.0
1.5
2.0
1.5
0.3
0.6
0.9
0.6
0.6
0.6
0.6
0.6
rt
19
19
19
19
24
24
24
24
21
28
30
49
74
52
58
64
rt
rt
rt
60°C
60°C
80°C
80°C
c
4
c
5
c
6
c
7
c
8
Entrya
X
Y
T [°C]
t [h]
Yield 2a [%]b
1
2
3
1.5
1.5
1.5
2.0
2.0
1.5
2.0
1.5
0.3
0.6
0.9
0.6
0.6
0.6
0.6
0.6
rt
rt
rt
rt
60 °C
60 °C
80 °C
80 °C
19
19
19
19
24
24
24
24
21
28
30
49
74
52
58
64
c
4
c
5
c
6
c
7
c
8
a
b
c
Reagents and conditions: 1a (0.2 mmol, 1.0 eq), LiNTf
Yield determined via 1H NMR spectroscopy with Bu
Reaction was performed in 1,2-dichloroethane (DCE) (2 mL).
2
4 6 2 2
(X eq.), Bu NPF (Y eq.), CH Cl (2 mL).
6
as an internal standard.
4
NPF
3

M. Chuchmareva, C. Strauch, S. Schröder et al.
Tetrahedron Letters 74 (2021) 153173
the influence of the position of either electron-donating (1i–k) or
electron- withdrawing groups (1l–n) on the arene is less impor-
tant; only ortho-substitution with a methoxy group lead to a
diminished yield of 2k (17%). In line with our previous work,
alkynes 1i–k with electron-donating groups on the aromatic moi-
ety led to only average product formation despite the enhanced
positive charge delocalization. The strong stabilization may result
in an increased lifetime of the open vinyl cation, leading to side
products and decomposition. Nevertheless, the very electron-rich
heteroaromatic alkyne 1o was a suitable substrate (45%). Finally,
non-aryl substituted triflimide 2p was synthesized in moderate
yield (27%), emphasizing the efficiency of the assisted vinyl cation
formation. A limitation of the method is reached when the alkyne
substituent is a simple alkyl group. Its comparatively poor cation
stabilizing ability prohibits bromo alkyne protonation and no con-
version of these substrates was observed.
Scheme 2. Gram-scale synthesis of bromo vinyl triflimide 2a.
In our previous work, we performed extensive mechanistic
analysis showing that the mutual stabilization of the transition
states of alkyne protonation and C–N bond formation results in a
selective syn-addition [8]. Given that poor selectivity is expected
Scheme 3. Functionalization of 2a via iron catalyzed cross-coupling reaction.
this protocol with larger amounts of substrate, a gram-scale syn-
thesis (Scheme 2) was performed, yielding phenyl triflimide 2a in
an only slightly lower 64% yield.
for the predicted open a-aryl-b-halovinyl cation and the triflimide
adds selectively, yielding the (E)-bromo triflimide as the unrivaled
syn-addition product, strongly indicates that the reaction proceeds
effectively via the same mechanism of assisted vinyl cation
formation.
The efficient self-assembly of a supramolecular framework of
2
LiNTf and water is crucial for an efficient reaction. Such a process
As already stated above, very little is known about the reactivity
of vinyl triflimides. Bromo vinyl triflimides are completely unex-
plored, naturally, as this is the first protocol providing synthetic
access. Because it may demonstrate a first hint of their potential
as building blocks, the derivatization reaction that was necessary
to unambiguously prove the (E)-geometry of the olefin’s substitu-
tion pattern is shown in Scheme 3. In this reaction the bromine
moiety is substituted by a methyl group under preservation of
the stereo information in an iron catalyzed cross-coupling reaction
[42].
may be influenced by a multitude of factors and prove difficult in
reactions on increased scale. Hence, to verify the applicability of
Table 2
Scope of bromo vinyl triflimides.
Conclusion
In summary, our previously reported concept of assisted vinyl
cation formation proved suitable for an unprecedented stereose-
lective addition of an N-nucleophile to an open b-halovinyl cation.
At the same time, a rare case of haloalkyne protonation was real-
ized. Thereby, bromo vinyl triflimides have become synthetically
accessible for the first time.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
This paper is dedicated to Professor Stephen Martin in recogni-
tion of his immense impact to the Tetrahedron journals and to the
field of organic synthesis. We further thank Dr. Christoph Räuber
(
RWTH Aachen) for multiple 2D-NMR experiments.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153173.
The image shown in this table is not the latest version. Please use current
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