Vinyl Triflimides—A Case of Assisted Vinyl Cation Formation

Article abstract of DOI:10.1002/anie.201810916

A new concept for selectivity control in carbocation-driven reactions has been identified which allows for the chemo-, regio-, and stereoselective addition of nucleophiles to alkynes—assisted vinyl cation formation—enabled by a Li⁺-based supramolecular framework. Mechanistic analysis of a model complex (Li₂NTf₂⁺?3 H₂O) confirms that solely the formation of a complex between the incoming nucleophile and the transition state of the alkyne protonation is responsible for the resulting selective N addition to the vinyl cation. Into the bargain, a general, operationally simple synthetic procedure to previously inaccessible vinyl triflimides is provided.

Full text of DOI:10.1002/anie.201810916

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Accepted Article
Title: Vinyl Triflimides – a Case of Assisted Vinyl Cation Formation
Authors: Sebastian Schroeder, Christina Strauch, Niklas Gaelings, and
Meike Niggemann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810916
Angew. Chem. 10.1002/ange.201810916
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10.1002/anie.201810916
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COMMUNICATION
Vinyl Triflimides – a Case of Assisted Vinyl Cation Formation
S. Schroeder[a], C. Strauch[a], N. Gaelings[a], and Meike Niggemann*[a]
Abstract: A new concept for selectivity control in carbocation driven
reactions has been identified, which allows for the chemo-, regio- and
stereoselective addition of nucleophiles to alkynes: Assisted Vinyl
Cation Formation, enabled by a Li+-based supramolecular framework.
Mechanistic analysis of a model complex (Li2NTf2+ · 3 H2O) confirms,
that solely the formation of a complex of the transition state of the
alkyne protonation with the incoming nucleophile is responsible for the
resulting selective N-addition to the vinyl cation. Into the bargain, a
general synthetic procedure to previously inaccessible vinyl triflimides
is provided, via an operationally simple protocol.
To test this hypothesis and validate the Assisted Vinyl Cation
Formation’s capacities for inducing selectivity, we chose a
seriously challenged borderline case, which, if effective may
demonstrate its generality. We turned to the direct hydroamino-
sulfonation of alkynes with trifluoromethanesulfonimide (HNTf2) in
Scheme 1. Although promising in its simplicity, such a reaction
suffers from several problems, and has therefore never been
realized. Stoichiometric amounts of the superacid HNTf2
undeniably cause poor functional group tolerance, with the
protonation of most functionalities being favoured over the
alkyne’s. The bistriflimide anion (TFSI) is a very poor nucleophile,
on account of the heavily delocalized nature of its electron
pairs.[10] It is well known for its innocent, non-nucleophilic
character as a counteranion. Nevertheless, a few scattered
reports indicate for the possibility of its addition to electrophiles[11]
such as phenyl cations,[12] vinyl cations[13] and ketenium ions.[14]
These reports evidence that regioselectivity is a third challenge.
O-addition, of a sulfonyl O-atom, is clearly preferred[13] and
mechanistic rationales, let alone studies, of what governs the
selectivity are lacking. Finally, a vinyl triflimide with a defined
olefin geometry is desirable. Even though the situation is further
complicated by equilibration reactions[15] and deviation from the
SN1-type mechanism,[13,16] additions of nucleophiles to vinyl
cations are controlled largely by steric effects.[17] Hence, even if
any selectivity occurs, it is heavily substrate-dependent and thus
unpredictable.
Carbocations are reactive intermediates that drive many transfor-
mations in synthetic chemistry. Most prominently they are
engaged by enzymes, such as terpene synthases, to selectively
build multicyclic skeletons from acyclic precursors.[1] Neverthe-
less, selectivity guiding principles for carbocation intermediates
remain rather elusive in chemical laboratory settings, even after a
century of cation research has passed. This may be accounted
for by the following reasons: Implementation of conformational
preorganization, as resorted to by the enzymes for inducing
selectivity, is in its infancy in synthetic chemistry.[2] Catalysts used
for cation generation dissociate from the cation, and are no longer
present for the selectivity determining bond formation.[3] Com-
bining a cation with a counteranion was successful for a handful
of special cases,[4] but never developed into a general principle.
A special member of the carbocation family, the vinyl cation was
long regarded as a misbehaved younger sibling of the more
prototypical trivalent carbocations. Despite its interesting
carbene-like reactivity,[5] little attention has been paid to the
development of synthetic methodology.[6] This is certainly due to
the widespread misconception, that vinyl cations were highly
reactive, uncontrollable reactive intermediates. This myth, that
originated in the slow reaction rate = high reactivity/low stability
paradigm, established for cations according to Hammond’s
postulate, was finally debunked by a fundamental study in 2017.[7]
It was found, that their stability is similar to trivalent cations and
the slow reaction rate of their solvolysis reactions merely a result
of a high intrinsic barrier for the energetic penalty of C-rehybridi-
zation (sp2 ↔ sp). This also explains, why they are so difficult to
generate.[8] Fortunately, this curse does not come without a
blessing. We hypothesize, that it is indeed the vinyl cation’s
reluctance to form, that may be used to induce selectivity towards
a single nucleophile among others.[9] This nucleophile must form
a stabilizing complex with the transition state (TS) of the vinyl
cation formation by transferring electron density into the nascent
p-orbital. It thus becomes obviously the first in line as a reaction
partner in what we term an “Assisted Vinyl Cation Formation”. A
cation that is easier to form does not require the additional
stabilization, forms randomly and reacts with the first nucleophile
encountered.
Scheme 1: a) Hydroaminosulfonation of alkynes; b) Model of a predicted
complex of the incoming nucleophile with the TS of alkyne ionization:
LiNTf2 · 2 H2O with a nascent vinyl cation.
Considering all of the above, we developed an enzyme mimicking
synthetic approach, in which the vinyl cation is generated within a
supramolecular framework, which shall guide the Assisted Vinyl
Cation Formation.[2a,18] Thereby, selectivity will be achieved, not
only for alkyne protonation and TFSI among other, more electron
rich nucleophiles (H2O, arene, product), but also for the less
favored N-atom within TFSI. Lithium was chosen as a templating
metal, for LiNTf2 is among the most readily available TFSI sources.
[a]
S. Schroeder, C. Strauch, N. Gaelings, Prof. Dr. M. Niggemann
Institute of Organic Chemistry, RWTH Aachen
Landoltweg 1, 52072 Aachen
E-mail: niggemann@oc.rwth-aachen.de
In addition,
a recent report highlights the importance of
stoichiometric Li+ for a selective TFSI addition.[12c] In a complex
Supporting information for this article is given via a link at the
end of the document.
with Li+, in solution, the TFSI anion adopts a cis-conformation and
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COMMUNICATION
is bound to Li+ in a 2-O,O’-mode.[19] As Li+-Ions strive for a
coordination number of 4-6 in non-aqueous solution,[20] it is
typically further coordinated to additional TFSI, solvent molecules,
or water. Finally, (trace) water molecules are known to
significantly impact the outcome of self assembly processes[21]
and to enhance the formation and stability of alkaline earth metal
complexes.[22] To our delight, in a model complex as shown in
Scheme 1 - LiNTf2 · 2 H2O with a nascent vinyl cation - atomic
distances are: 1.) Favourable for the transfer of a proton from one
of the Li+-coordinated water molecules. 2.) The N-Atom in TFSI is
perfectly positioned for the Assisted Vinyl Cation Formation, and
thus selective N-addition. Given the geometry of the predicted TS
complex, a stereoselective syn-addition, independent of the
substituents’ sterics, is expected as a bonus.
Table 1. Optimization.
Entry
X
Y
Z
additive
2 [%]
3 [%]
1
2
3
4
5
6
1.5
1.5
1.5
-
1.5
1.5
-
0.3
0.3
-
0.3
-
-
-
-
-
-
0
47
4
0
4
0
MS 4Å
1.5
0.1
0.5/0.1
Bu4NNTf2
CSA
0
57
52
0
2
48
CSA/PhMe2HN+
B(C6F5)4 ˉ
CSA
7
8
9
1
1.5
3
0.1
1
1.5
0.5
44
70
1
9
CSA
0.1
0.3
0.3
0.3
0.3
0.3
0.3
-
3
CSA
31
2
10[a]
11[a,b]
12[a]
13[a]
14[a,c]
15[a,d]
16
5
0.5
0.5
CSA
CSA
67
35
60
76
80
99
traces
13
12
7
24
20
1
Our search for conditions that allow for the self-assembly of a
complex like the one in Scheme 1, started with the addition of
phenylacetylene 1 to a solution of 1 equiv LiNTf2 in dichloro-
methane (Table 1, entry 1). But it was not before we added
Bu4NPF6, to improve the solubility of LiNTf2
1.5
1.5
1.5
1.5
1.5
-
0.5/2
0.5/1.0
0.5/1.0
0.5/1.0
1.25
CSA/KPF6
CSA/LiPF6
CSA/LiPF6
CSA/LiPF6
HNTf2
[12c]
-
that we first
observed the vinyl triflimide 2 in 47% yield (Table 1, entry 2). The
regioselectivity of the addition is governed by the cation stabilizing
effect of the -aryl substituent.[23] Exclusion of water with
molecular sieves, or the absence of Li+ results in inhibition
(Table 1, entry 3/4). In line with the model in Scheme 1, this
highlights the important role of water and Li+. Among many proton
donors tested, camphorsulfonic acid (CSA, entry 5, others not
shown) slightly improves the results.[24] The variation of additives
(e.g. Bu4NSbF6, Bu4NBF4, etc.) identified only PhMe2HN+B(C6F5)4ˉ
to allow for a satisfactory conversion, albeit with poor selectivity
for N-addition. Significant amounts of acetophenone 3, as a
product of an O-addition-hydrolysis sequence were observed
(entry 6, others not shown). Further improvement was achieved
by an extensive screening of stoichiometries, solvents and
concentrations (exemplary results: entries 7-10). At this stage, the
influence of water was investigated once more. In its absence
(molecular sieves), the reaction ceases (not shown). Saturating
[a] c = 0.33 M, [b] solvent saturated with water, [c] a solution of all other
reagents stirred 1h before addition of 1, [d] 24h stirring before addition of 1.
the solvent (DCM) with water, results in a drop of conversion,
indicating for inefficient formation of the supramolecular
framework (Table 1, entry 11). Increasing the amount of Li+ via
the addition of 1 equiv LiPF6 further enhances the conversion, but
again decreases the selectivity (Table 1, entry 13). The
N-selectivity was restored by prolonged stirring of the solution
before the addition of 1. This presumably allows for an
equilibration of the self-assembled supramolecular framework.
The best results were obtained after 24h of stirring time for
complex equilibration (entry 15). For comparison, a reaction of
HNTf2 with phenylacetylene 1, resulting in rapid decomposition of
the starting material, is also included (Table 1, entry 16).
Table 2. Scope of the Hydroaminosulfonation.
Conditions: 1.5 equiv LiNTf2, 0.3 equiv Bu4NPF6, and 0.5 equiv LiPF6 were stirred for 24 hours at rt in 0.6 ml (0.33M) dichloromethane. Alkyne 4 (0.2 mmol) was
added and stirring was continued for an additional 21 hours. [a] 1 hour stirring before addition of alkyne 4; [b] 0.5 equiv CSA added; [c] 85°C, 1,2-dichloroethane;
[d] TMS-protected acetylene used as precursor; * E:Z ratio determined by NMR-spectroscopic analysis.
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We turned to evaluating the scope. As their vinyl cation
intermediates are well stabilized[23] -aryl substituted terminal
alkynes 4 gave vinyl triflimides 5 with excellent selectivity and
yields (Table 2, entry 5a-q). The best results were obtained for
alkynes 4 with moderately electron poor aryl groups, as
unassisted background vinyl cation formation, leading to O-
addition of TFSI, begins to interfere when the alkyne bears
electron rich aryl substituents (entry 5c-h). Consistent with our
expectations and the mechanism discussed below, vinyl triflimide
formation proceeds via a syn-addition for internal alkynes, again
with excellent chemo- and regioselectivity (entry 5r-y). Owing to
the poor stabilization provided by -vinyl or even -alkyl
substituents, such vinyl cations are notoriously difficult to
generate. Intermolecular reactions require either elaborate
starting materials[13] or catalysts.[5a] Therefore, it is remarkable
that the Assisted Vinyl Cation Formation enables such reactions,
albeit with moderate yields (entry 5z-ad). Intrigued by the finding
that olefin moieties remained intact (entry 5z/aa), a competition
experiment was run to confirm the reactions selectivity for the
alkyne (Scheme 2).
positively charged vinyl cation-like TS. In the following, an easily
applicable strategy for its confirmation is provided. In addition, the
following key questions shall be answered:
1.) Is really a complex with the TS of the vinyl cation formation
responsible for the observed reactivity and selectivity?
2.) Why is Li+ required for an efficient formation of that complex?
A prerequisite for further analyses of reaction determining TSs is
a viable reaction pathway. Even though quasi-classical molecular
dynamic calculations are more accurate for the analysis of the
relatively flat regions of the energy surface in cation chemistry,[25]
conventional transition state theory should be sufficient to gain a
qualitative picture of reactivity,[26] and thus to answer the question
whether or not coordination of the nucleophile to the TS occurs.
Extensive initial trials with complexes of different compositions
revealed the model complex of TFSI with 2 Li+ ions and 3 H2O in
Figure 1 to represent the lowest level of complexity that allows for
the computation of a reaction coordinate all the way from the
reactants to product 2. Although the reaction path is unusual with
a prelocated shoulder, it is free of intermediates and all barriers
are realistic (see SI).[27] This complex is obviously just a truncated
model of what the certainly oligomeric structure[19a,19e] may look
like, but given the important roles of H2O and additional Li+ on the
reaction outcome, it may be a good compromise, providing
realistic results at acceptable computational costs. In this model,
the proton for the alkyne ionization originates from a water
molecule that is acidified by the coordination to both of the Li+ ions.
To confirm the complex of the incoming nucleophile with the TS
for the alkyne protonation, we turned to NBO analysis of various
structures along the computed reaction path.[28] The TS is indeed
stabilized by a hyperconjugation of both of the TFSI’s nitrogen
lone pairs into the nascent p-orbital of the vinyl cation (Figure 3,
B1 and B2). After the ionization this hyperconjugation intensifies
(C1, C2) until coalescing into the TS of C-N bond closure (D1, D2).
It occurs with a barrier of only 3.2 kcal/mol, due to a strong
stabilization provided by a hydrogen bridge (D3),[29] that is the
reminder of the acidic O-H bond, the protagonist of the first TS.
Thus, both TSs mutually stabilize each other, resulting in a
reduced activation energy for the whole process. This also
explains the observed selectivities, for reaction only occurs if both
Scheme 2: Competition experiments in the presence of olefins. [a] Determined
by gas-chromatographic analysis.
TFSI addition to olefins was not observed. Apart from minor
amounts of decomposition, again ascribed to background
reactions, the olefins in 7a / 7b remained unaffected.
For a better understanding of the mechanism we turned to DFT
based computational analysis. We are certain that Assisted Vinyl
Cation Formation is a general phenomenon, which may contribute
to (unexpected) selectivity in all reactions that proceed via a
Figure 1. Hyperconjugative energies of NBO’s were analyzed for various structures (model complex Li2NTf2+ · 3 H2O with alkyne 1; M06-2X/6-31+G(d,p)) along the
reaction coordinate (see SI). The NBO 3.1 program was used to analyse selected structures and stationary points[28] Molecules and orbitals were rendered with
Avogadro 1.2.0. Selected hyperconjugative energies are displayed in kcal/mol.
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