Taming a Vinyl Cation with a Simple Al(OTf)3 Catalyst To Promote C?C Bond Cleavage

Article abstract of DOI:10.1002/chem.201700282

A detailed mechanistic investigation identified the stepwise nature of the 1,3-aryl shift, which enables our recently disclosed Al³⁺-catalyzed insertion of unactivated alkynes into the sp²–sp³ C?C bond of benzyl alcohols. The selectivity for the rearranged product was found to be induced by the continued coordination of the aluminum catalyst to the rearranging species, which is encouraged by a reversible background reaction. This participation of the catalyst beyond the ionization step is unique in the realm of carbocation driven reactions and opens up the possibility of a catalyst-induced chiral induction in the future. Furthermore, the study represents a rare example of detailed mechanistic analysis of a reaction with a product selectivity that changes with increasing conversion.

Full text of DOI:10.1002/chem.201700282

A Journal of
Accepted Article
Title: How to Tame a Vinyl Cation with a Simple Al(OTf)3 Catalyst - so
that it Promotes a C-C Bond Cleavage
Authors: Meike Niggemann, Liang Fu, and Helena Damsen
This manuscript has been accepted after peer review and appears as an
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To be cited as: Chem. Eur. J. 10.1002/chem.201700282
Link to VoR: http://dx.doi.org/10.1002/chem.201700282
Supported by

10.1002/chem.201700282
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How to Tame a Vinyl Cation with a Simple Al(OTf)3 Catalyst -
so that it Promotes a C-C Bond Cleavage
Meike Niggemann*[a], Liang Fu,[a] and Helena Damsen [a]
Abstract: Detailed mechanistic investigation identified the stepwise
nature of the 1,3-aryl shift, which enables our recently disclosed Al3+-
catalyzed insertion of unactivated alkynes into the sp2-sp3 C-C bond
of benzyl alcohols. The selectivity for the rearranged product was
found to be induced by the continued coordination of the aluminum
catalyst to the rearranging species, which is encouraged by a
reversible background reaction. This participation of the catalyst
beyond the ionization step is unique in the realm of carbocation
driven reactions and opens up the possibility of catalyst induced
chiral induction in the future. Furthermore, the study represents a
rare example of detailed mechanistic analysis of a reaction with a
product selectivity that changes with increasing conversion.
o-amino as well as o-hydroxy benzylic alcohols 1 (Scheme 1) -
in the absence of any transition metal and/or stoichiometric
oxidant, enabled by nothing more than a simple aluminum based
Lewis acidic catalyst.
Scheme 1. Vinyl cation reactivity based C-C bond cleavage.
Vinyl cations are among the most special reactive intermediates
known to propel organic reactions1 and therefore, undoubtedly,
bear great potential for the discovery of new reaction pathways.
Their high reactivity, nevertheless, comes along with several, as
yet mostly unsolved challenges, despite the fact that vinyl
cations have been proposed as reactive intermediates,2 quite a
long time ago. These challenges start with the formation of vinyl
cations. Traditionally, chemists had to rely upon the protonation
of alkynes with super-acids,3 fragmentation of elaborate
precursors such as iodonium salts4 or the often incomplete
solvolysis of triflates in the presence of large excesses of the
nucleophilic reaction partner under harsh conditions.5 The
challenge then continues, as once formed, vinyl cations react,
not unlike radical species, rather indiscriminate with any organic
molecule, also solvents, at an almost diffusion controlled
reaction speed. So that, powerful driving forces are needed for a
predictable reaction outcome, selective product formation and
the prevention of undesired side reactions.
To contribute to a better understanding of vinyl cation driven
reactions, this unprecedented skeletal rearrangement intrigued
us also from a mechanistic point of view, and we herewith
present our efforts towards the elucidation of the mechanism of
this unusual transformation.
These challenges overcome, the application of vinyl cation
reactivity provides highly attractive perspectives for the
realization of unprecedented and complex transformations within
the rapidly growing field of transition metal free reactions. Of
particular interest in this context are carbocation cascade
reactions, often encompassing multiple elementary mechanistic
steps. Hence, a deeper understanding of the nature of vinyl
cation driven reactions – first and foremost with regard to the
factors controlling reaction selectivity - sets the stage for future
reaction design in the field.
As a new reaction cascade for a vinyl cation intermediate we
recently discovered a vinyl cation to allyl cation rearrangement
(A  B, Schemes 1/2) as a driving force for an unprecedented
1,3-aryl carbon shift reaction.6 This was used for the
development of a new type of transition-metal free C-C bond
cleavage reaction.7 The transformation allows for a net insertion
of internal, unactivated alkynes 2 into the sp2-sp3 C-C bond of
Scheme 2. Formation and reactivity of vinyl cation intermediate A.
A general outline of the main reaction pathways to and from the
vinyl cation key intermediate is shown in Scheme 2. In analogy
to our previous work,8
a classical Lewis acid catalyzed
dehydration of benzyl alcohol 1 yields the benzylic cation I+. This
is attacked by the alkyne moiety in 2 to form the vinyl cation key
intermediate A. For the following, on behalf of its high reactivity
certainly intramolecular reaction step, A is presented with 3
alternatives. Apart from the observed 1,3-aryl shift to B and its
subsequent cyclization with the nucleophilic substituent in the
arene (pathway a), A could also directly cyclize with the same
nucleophile (pathway b).9 In addition, a Friedel-Crafts reaction at
[a]
Dr. L. Fu, Dr. H. Damsen, Prof. Dr. M. Niggemann
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: niggemann@oc.rwth-aachen.de
Supporting information for this article is given via a link at the end of
the document
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10.1002/chem.201700282
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the nucleophilic substituents m-position could yield indene 5
(pathway c).10,11
This rationalizes why a F-C reaction, if occurring, is selective for
pathway a over c, but why is it favored over a direct cyclization
of the initially formed vinyl cation with the nitrogen nucleophile
(pathway b)? An answer to this question was sought for by DFT-
based computational analysis. These studies were performed
with a focus on the o-NHTos benzyl alcohols, with a model
system of 1a (Nu = NHTos; R1 = Me) and alkyne 2a (Ar = Ph;
R2 = Me), as the selectivity for the rearrangement was generally
more pronounced for the insertion into o-NHTos than o-hydroxyl
benzyl alcohols. In this inaugural study, catalyst participation
beyond the ionization step was not considered, as in most
carbocation driven mechanisms and all our previous mechanistic
analyses the catalyst plays no further role beyond the formation
of the initial carbocation species, the benzyl cation I+. In addition,
insight into the behaviour/electronic nature of the carbocationic
reactive intermediates themselves is thereby provided. DFT
calculations confirm that the 1,3-aryl shift occurs via the
stepwise pathway proposed in Scheme 3 (Figure 1). Surprisingly,
in a comparative analysis of the alternative reaction pathway b -
the direct nucleophilic addition of the nitrogen atom to the vinyl
cation - energies were found to lay within the same range. For a
more detailed analysis, depictions of selected structures, full
size energy profiles and an evaluation of the computational
methods we refer to the supporting information.
Ultimately, the studies presented herein shall provide answers to
the following key questions, regarding the fate of the vinyl cation:
1.) Why is the rearranged reaction product 3 formed selectively
- at the expanse of the direct cyclization product 4 and the
indene 5?
2.) What is the exact nature of the 1,3-aryl shift - and is it really
cation driven?
3.) Why is Al(OTf)3 the best catalyst for a selective formation of
product C? Does it play a role beyond the ionization of the
benzyl alcohol 1?
The initiating ionization process can theoretically be
accomplished by a range of Lewis / Bronstedt acid catalysts12 as
the dehydration of a benzylic alcohol is comparatively easy.
During the optimization studies a combination of 10 mol %
Al(OTf)3 with an additive of an ammonium salt of a weekly
coordinating anion, such as Bu4NPF6, were most effective at
providing selectivity towards the desired rearranged cyclization
product 3, preventing oligomerization and elimination of benzyl
alcohol 1 and ensuring its complete conversion. Albeit being
able to ionize the benzylic alcohol, other Lewis/Bronsted acids,
e.g. In(OTf)3, Ca(NTf2)2 or HOTf gave diminished selectivities for
the rearranged product 3 and poor yields.
The products of pathways a and b were both regularly
encountered, in different ratios, during the optimization studies,
whereas indene 5 resulting from a direct F-C type ring closure
(pathway c) was never isolated. This preference is easily
rationalized. Both substituents, the NHTos as well as the OH,13
have pronounced o,p-directing properties due to the possibility
to accommodate a positive charge at the heteroatom of the
substituent in the initial Wheland intermediate. Therefore, when
electron density is transferred from the aromatic core to the
empty p-orbital of the vinyl cation, a bond will establish in the
ipso position rather than the meta, if the penalty for the formation
of the four membered ring in D is not too high (see Scheme 3).14
In other words, the process of “attacking” the vinyl cation is the
same leading to 7 or the 4-membered ring containing D, it simply
diverges at some point to form the more stable product, which is
the 4-membered ring containing D in this case, due to the
destabilizing effect of the NHTos/OH in the Wheyland
intermediate on the way to 7.This process, in fact, is highly
analogous to the first step in an arene 1,2-shift in a classical
Wagner-Meerwein reaction, which proceeds via the 3-
membered phenonium ion C.15
Figure 1. Computed energies (mPW1PW91/6-31+G(d,p)) for the selectivity
determining key steps without catalyst participation (green - major product, red
- minor product).
Hence, both the cation driven stepwise 1,3-aryl shift (pathway a)
as well as the direct cyclization (pathway b) clearly are
energetically accessible, but selectivity for one or the other is
unexpected and a mixture of products would be consistent with
the computational results. Consequently, the origin of the
observed selectivity is not to be found solely in the electronic
structure of the vinyl cation key intermediate.
Furthermore, determination of the product selectivity over time
reveals, that selectivity improves with increasing conversion of
the starting materials. From a meagre 2:1 selectivity at ~ 5 %
conversion, that more or less matches the outcome of the
computational analysis, a selectivity of 95:5 is reached at the
end of the reaction (Figure 2). Isolation of both products 3a, and
4a and re-subjection to the reaction conditions shows no
interconversion between the two. Nor is one of them
decomposed selectively upon extended reaction times. This
Scheme 3. Comparison of cationic 1,2- and 1,3-aryl shift.
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finding further supports the fact that the origin of the selectivity
cannot be found in the electronic structure of the vinyl cation
intermediate, as it should be the same at the beginning and the
end of the reaction.
to simply break down into the equilibrating species and reiterate
into the original reaction. Overall, this indicates, that selectivity
for product 3a over 4a is achieved over time, as more and more
of the ether 6a is formed and directly converted into product 3a.
Scheme 5. Control experiments I.
Figure 2. Product selectivity with increasing conversion.
Ether 6a /Amine 6b’ (0.3 mmol), alkyne 2a (0.36 mmol) and 5 mol% Bu4NPF6
were added at rt to 10 mol % Al(OTf)3 in 1.5 mL DCE and stirred for 12 h at
40 °C; Ratio 3a:4a determined by NMR spectroscopic analysis of the crude
mixture; Isolated yields.
Alcohol 1a (0.3 mmol), alkyne 2a (0.36 mmol) and 5 mol% Bu4NPF6 were
added at rt to 10 mol% Al(OTf)3 in 1.5 mL of DCE and stirred at 40 °C. At
intervals samples were withdrawn and subjected to NMR-spectroscopic
analysis after work-up.
A potential explanation for the selectivity inducing effect of the
ether 6a might be found in an entirely different reaction
mechanism.
Also, the analysis of the reaction mixture at various times prior to
completion indicates for a complex equilibrium between various
species that are formed in reversible background reactions. In
these, the initially formed cation I+ reacts with a further benzyl
alcohol molecule 1a, yielding ether 6a when attacked by the
hydroxyl moiety, or amine 6b upon reaction with the benzyl
alcohols nitrogen atom (Scheme 4). The ether 6a was found to
largely predominate throughout the reaction,16 which might be
assigned to both, the electron withdrawing properties of the tosyl
group in 1a, lowering the nucleophilicy of the nitrogen and steric
crowding around it.
Scheme 6. Retro-Friedel-Crafts / Povarov pathway.
Ionization of the benzyl alcohol 1a is much easier for the catalyst
than (re-)ionization of the ether 6a. Therefore, it is conceivable
that the ionization of this species needs further assistance by the
merging of the ionization with a second, energetically more
favorable process such as the nucleophilic attack of the adjacent
nitrogen atom, leading to the dihydroazetium cation in V+
(Scheme 6). This might rearrange to the iminium ion VI+ via a
1,3-hydride shift followed by a retro F-C type process. Thus
generated iminium VII+ might yield vinyl cation VIII+ upon
nucleophilic addition of the alkyne moiety followed by ring
closure to 1,2-dihydroquinoline 3a in analogy to a Povarov
reaction.17 To probe this alternative reaction mechanism two
simple control experiments were performed (Scheme 7). In
these, the iminium ion VII+ - key intermediate in the alternative
reaction pathway in Scheme 6 - is synthesized either by the in-
situ condensation of aniline 7 with aldehyde 8 or the ionization of
aminal 9 under otherwise identical reaction conditions. Both
reactions yielded none of the previously obtained products 3a
and 4a, but gave clean conversion to the ,-unsaturated ketone
10 in a carbonyl alkyne metathesis process.18 Hence, it is very
Scheme 4. Reversible Background Reaction
Deduced by HPLC/ NMR analysis of reaction mixture after 2 h, 4 h and 6 h,
corresponding to 18 %, 35 % and 55 % conversion.
For an analysis of their influence on the product selectivity, ether
6a was isolated, and amine 6b’ was synthesized (isolation of
amine 6b in the required amounts proved impossible). The two
were subjected to the reaction conditions in the presence of the
alkyne 2a (Scheme 5). Much to our surprise, it is the ether, that
yields the rearranged 1,2-dihydroquinoline 3a with excellent
selectivity without further detouring to any of the equilibrium
species, albeit in a much longer reaction time. To reinforce this
finding the corresponding methyl ether (OMe instead of OH in
1a) was synthesized and subjected to the reaction conditions
with an analogous result (not shown). The amine 6b’ was found
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unlikely that a retro-F-C / Povarov mechanism is involved in our
C-C bond cleavage.
neutral cyclobutenone IIIn,23 thus providing a reaction pathway
that parallels the ionic dearomatization-rearomatization cascade
towards 3a in Scheme 3. Transition states for these potential
reaction pathways were located computationally, clearly
demonstrating that the activation barriers for these pericyclic
reactions are energetically higher (by ~ 10 kcal/mol) than for the
cationic pathways described above. This confirms a carbocation
driven mechanism (see s.i. for further discussion). In addition, no
selectivity for the [2+2] over the [4+2] would be expected from
the results.
Scheme 7. Control experiments II.
Aniline 7 (0.3 mmol), aldehyde 8 (0.36 mmol) / aminal 9 (0.3 mmol), alkyne 2a
(0.36 mmol) and 5 mol% Bu4NPF6 were added at rt to 10 mol% Al(OTf)3 in
1.5 mL DCE and stirred for 12 h at 40 °C; Isolated yields.
Next, a potential difference in reaction initiation was examined,
comparing the ionizations of ether 6a and alcohol 1a.
Figure 3. Electrostatic potential surfaces of 11Al and I+Al
.
Blue - electropositive, green - neutral, red - electronegative.
Finally, an analysis of the electrostatic potential surface of 11Al
(Figure 3) reveals a charge separation in the molecule –
negative charge on two oxygens in one of the triflate anions and
positive charge in the arene system - as a result of the Lewis
acidity of the aluminum catalyst. This is also reflected in the
slightly elongated bond between aluminum and the triflate anion
in the trans-position to the nitrogen atom in 11Al. The negative
charge in this triflate anion makes it highly prone to protonation,
which in turn induces its departure from the complex with an
activation barrier of only 6.3 kcal/mol.
Scheme 8. Aluminum catalyzed ionization of ether 6a.
The aluminum catalyst coordinates to alcohol 1a at the hydroxyl
moiety and thereby induces dehydration to yield the
corresponding benzyl cation I+. In ether 6a coordination to the
nitrogen atom, leading to the chelated aluminum in IX
(Scheme 8), followed by ether cleavage in a 6-membered
transition state, yielding the uncharged o-azaquinone methide
11Al is more likely.19 Alternatively, a disproportionation of the
Al(OTf)3 catalyst into Al(OTf)2+ and Al(OTf)4- followed by chelate
formation and deprotonation, thus also yielding IX and
subsequently 11Al in analogy to Yu’s work is also conceivable.20
This is backed up by computational analysis (see s. i. for further
discussion). The prevailing formation of 11Al represents a
potential diversion into cycloaddition pathways (Scheme 9).21
Scheme 9. Pericyclic reactions of o-azaquinone methide 11.
Hence, with or without prior decoordination of the aluminum
catalyst, the o-azaquinone methide 11 can react in a hetero
Diels-Alder type [4+2] reaction22 yielding again 1,4-dihydro-
Figure 4. Computed energies (mPW1PW91/ 6-31+G(d,p)) for the selectivity
determining key steps with catalyst participation (green - major product, red -
minor product).
quinoline 4a. Alternatively,
a geometrically forbidden yet
thermally allowed [π2s+π2a] cycloaddition directly accesses the
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The overall process transforms the catalyst bound o-azaquinone
methide 11Al to the benzyl cation I+Al, still coordinated to the
aluminum catalyst. The energetic penalties for both, a catalyst
decoordination and catalyst enhanced cycloaddition reactions
were found to be higher (see s. i. for further details). Bearing a
highly pronounced positive charge at the benzylic position, this
species is now ideally suited for a nucleophilic addition of the
poorly nucleophilic alkyne 2a (Figure 3).
Selectivity for the rearranged product 3a is poor at low
conversion rates and increases to ~20:1 towards the end of the
reaction. Both, cation reactivity based (starting from I+, Schemes
2+3) and cycloaddition pathways (starting from 11, Scheme 9)
are energetically accessible with and without further catalyst
participation. The activation barrier for the addition of the alkyne,
the first and rate determining step in all reaction pathways, is
generally lower by ~ 10 kcal/mol in the ionic pathways. For
reactions uncatalyzed beyond the ionization step, no clear
preference for either the direct cyclization (pathway b) or the
rearrangement-cyclization (pathway a) was determined. This
changes dramatically when catalyst participation beyond the
initial ionization step is taken into account, as the direct
cyclization pathway is blocked (or strongly discouraged) by the
catalysts coordination to the nucleophilic nitrogen atom. The
preference for a mechanism with catalyst participation beyond
the ionization step, and hence selectivity, is ultimately achieved
indirectly by a background reaction leading to the formation of
ether 6a. Ionization of this ether predominantly leads to the
formation of the aluminum coordinated o-azaquinone methide
11Al, HOTf departure from which results in the generation of the
aluminum catalyst bound benzyl cation I+Al. Addition of the
alkyne 2a generates vinyl cation IIa+Al, that is rearranged to the
allyl cation IV+Al in a stepwise process. This species, uncharged
after hydrolysis induced decoordination of the catalyst, is
subjected to electrocyclic ring closure to the final product 3a
(see s.i. for further details). This mechanistic picture also nicely
accommodates the superior selectivity found for the Al3+ catalyst
compared to other Lewis acids such as Ca2+, Li+ or Mg2+, as
these form much weaker and more fluctional coordinative bonds
with nitrogen atoms. Thereby continued catalyst participation
would be easily interrupted with these catalysts.
C-C: 2.03 Å
C-N: 2.20 Å
TS  III+Al
TS  4a+Al
Figure 5. Structures of the transition states to III+Al and 4a+Al
.
In the thus induced ionic pathway with catalyst participation the
continued Al-coordination at the nitrogen atom provokes steric
clash (Figure 5) and drastically lowers its nucleophilicity.
Thereby, the energy gap between the ipso-F-C process and the
direct nucleophilic addition of the nitrogen to the vinyl cation is
increased in favour of the ring closure to the 4-membered ring in
III+Al (Figure 4). In addition, the ring closure - ring opening
sequence is merged into a quasi-concerted process by the
catalyst’s presence, so that the reaction proceeds all the way to
the allyl cation IV+Al once the ring closure to the 4-membered
ring in III+Al has occurred.
Bundling up all experimental and computational results we came
to the following conclusions leading to the final proposed
mechanism in Scheme 10:
Acknowledgements
We thank the China Scholarship Council (CSC) for financial
support of Liang Fu.
Keywords: carbon shift • transition metal free • cation
rearrangement • aluminum catalysis • vinyl cation
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Scheme 10. Proposed catalytic cycle.
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10.1002/chem.201700282
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Hold on aluminum! Continued partici-
pation of the catalyst in a carbocation
driven reaction proved responsible for
the selective induction of a highly
unusual 1,3-carbon shift. Detailed
mechanistic analysis explains why a
vinyl cation undergoes an unexpected
rearrangement, resulting in the net
insertion of unactivated alkynes into a
C-C bond in benzylic alcohols.
Meike Niggemann*, Liang Fu, and
Helena Damsen
Page No. – Page No.
How to Tame a Vinyl Cation with a
Simple Al(OTf)3 Catalyst - so that it
Promotes a C-C Bond Cleavage
This article is protected by copyright. All rights reserved.