Br?nsted Acid-Catalyzed Carbonyl-Olefin Metathesis inside a Self-Assembled Supramolecular Host

Article abstract of DOI:10.1002/anie.201712141

Carbonyl–olefin metathesis represents a powerful yet underdeveloped method for the formation of carbon–carbon bonds. So far, no Br?nsted acid based method for the catalytic carbonyl–olefin metathesis has been described. Herein, a cocatalytic system based on a simple Br?nsted acid (HCl) and a self-assembled supramolecular host is presented. The developed system compares well with the current benchmark catalyst for carbonyl–olefin metathesis in terms of substrate scope and yield of isolated product. Control experiments provide strong evidence that the reaction proceeds inside the cavity of the supramolecular host. A mechanistic probe indicates that a stepwise reaction mechanism is likely.

Full text of DOI:10.1002/anie.201712141

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Accepted Article
Title: Brønsted Acid-Catalyzed Carbonyl-Olefin Metathesis inside a
Self-Assembled Supramolecular Host
Authors: Lorenzo Catti and Konrad Tiefenbacher
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712141
Angew. Chem. 10.1002/ange.201712141
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10.1002/anie.201712141
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Brønsted Acid-Catalyzed Carbonyl-Olefin Metathesis inside
a Self-Assembled Supramolecular Host
Lorenzo Catti[a] and Konrad Tiefenbacher*[a,b]
Abstract: Carbonyl-olefin metathesis represents a powerful, yet
underdeveloped, method for the formation of carbon-carbon bonds.
So far, no Brønsted acid-based protocol for the catalytic carbonyl-
olefin metathesis has been described in the literature. Herein, a
cocatalytic system based on a simple Brønsted acid (HCl) and a self-
assembled supramolecular host is presented. The developed system
compares well with the current benchmark catalyst for carbonyl-olefin
metathesis in terms of substrate scope and isolated product yield. The
control experiments performed provide strong evidence that the
reaction proceeds inside the cavity of the supramolecular host. A
mechanistic probe indicates that a stepwise reaction mechanism is
likely.
oxetane intermediate (Figure 1b). It is noteworthy that the
Schindler group performed a systematic study to exclude that the
reaction is catalyzed by HCl-traces, which might be formed by
hydrolysis of FeCl3. Even with 100 mol% of HCl, no conversion of
the employed substrate was observed.[9]
Figure 1. Carbonyl-olefin metathesis. a) Stoichiometric in transition metal. b)
Catalyzed by FeCl3. c) This work: catalyzed by HCl in the presence of a
supramolecular host.
Catalytic olefin metathesis is regarded as one of the most
powerful methods of carbon-carbon bond formation and has led
to significant advances in both academic and industrial
synthesis.[1] The related carbonyl-olefin metathesis has received
significantly less attention, despite its undisputable potential,
mainly due to the difficulty to establish a catalytic process.
Although olefin metathesis catalysts can also promote the
carbonyl-olefin metathesis,[2] turnover is prevented by the
formation of a kinetically inert metal-oxo complex during the
cycloreversion step (Figure 1a). Most protocols described depend
on stoichiometric amounts of Lewis acid.[3] In 2012, the Lambert
group disclosed an organocatalyzed ring-opening carbonyl-olefin
metathesis.[4] Although being a significant contribution, the
method is limited to cyclopropene derivatives as olefinic
components. In addition, a Lewis acid-catalyzed intermolecular
carbonyl-olefin metathesis was reported by Franzén et al. using
20 mol% of trityl tetrafluoroborate.[5] The reaction requires,
however, a fivefold excess of the carbonyl component and is
restricted in terms of substrate scope. Finally, in 2016, a
breakthrough in carbonyl-olefin metathesis was accomplished by
Schindler and coworkers utilizing catalytic amounts of FeCl3.[6]
The developed method displays a relatively broad substrate
scope, mild reaction conditions and operational simplicity.[6-7]
Shortly after, a similar approach was described by the Li group for
the construction of carbo- and heterocyclic alkenes.[8] Both
methods proceed via a [2+2] cycloreversion of an in situ formed
Supramolecular host systems are increasingly investigated
regarding their ability to facilitate reactions difficult to perform in
bulk solution.[10] The resorcin[4]arene hexamer I represents one
of the most investigated supramolecular host systems (Figure
2).[11] It spontaneously self-assembles via hydrogen bonding in
apolar solvents like chloroform from eight water molecules and six
resorcin[4]arene units 1,[12] which are easily prepared in multigram
scale in a single step. Hexamer I is believed to be capable of
stabilizing cationic transition states via cation- interactions with
the aromatic cavity walls.[12f] Recently we demonstrated that host
I forms a cocatalytic system with the Brønsted acid HCl to
catalyze the tail-to-head terpene cyclization,[13] a reaction that is
difficult to perform in bulk solution.[14] In addition, Scarso and
Strukul demonstrated that hexamer I and HBF4 work in a
synergistic fashion to catalyze the hydration of aryl alkynes.[15]
The ability of hexamer I to facilitate challenging reactions involving
Brønsted acids prompted us to investigate the catalytic activity of
the hexamer I/HCl system in the carbonyl-olefin metathesis.
Dr. L. Catti and Prof. Dr. K. Tiefenbacher
[a]
[b]
Department of Chemistry, University of Basel, BPR 1096,
PO Box 3350, Mattenstrasse 24a,
CH-4002 Basel, Switzerland
Department of Biosystems Science and Engineering, ETH Zurich,
Mattenstrasse 26,
CH-4058 Basel, Switzerland
E-mail: konrad.tiefenbacher@unibas.ch / tkonrad@ethz.ch
.
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10.1002/anie.201712141
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We next set out to compare the performance of this
supramolecular catalytic system with the current benchmark
catalyst FeCl3 in terms of substrate scope and product yield
(Table 2). The -methylstyryl substrate 4 was converted in good
yield, although at a slower reaction rate. We next investigated -
ketoamide 5, which gave cyclopentene 6 in 87% yield after 43
hours. It is noteworthy that amide 5 required stoichiometric
amounts of FeCl3 for full conversion, due to its increased Lewis
basicity. Conversion of -ketoesters with electron-rich arene
subunits (7, 9, 11) gave the corresponding cyclopentene
derivatives (8, 10, 12) in good to excellent yields. However, in the
case of an electron-donating substituent in the para-position,
protonation of the formed double bond was favored, resulting in a
mixture of alkene isomers. Isomerization of the newly formed
double bond was also occasionally observed by Schindler and
coworkers in their studies utilizing FeCl3.[6] In accordance with the
literature, the corresponding electron-poor chloroarene 13 proved
reluctant to undergo the metathesis reaction and additional HCl
was required to achieve a reasonable reaction time. The ,-
unsaturated ketones 15, 17 and 19 were converted cleanly to the
corresponding cyclopentenes (entries 8-10). Interestingly, the
obtained yields marked a significant improvement over the values
reported in the literature. Also, more rigid substrates like 21 and
23 were accommodated readily inside the large cavity of hexamer
I, yielding the corresponding polycyclic aromatic hydrocarbons 22
and 24 in good to excellent yields. The successful conversion of
substrate 25 furthermore demonstrated that, as previously
observed with substrate 15, bis-substitution in the -position is
tolerated well by the catalytic system and that the method is
suitable to access structurally more complex motifs like
spirolactone 26. Additionally, substrate 27 proved that the
cocatalytic system also provides access to cyclohexenes like 28.
Although FeCl3 performs better with some of the substrates, Table
2 clearly demonstrates that the cocatalytic system provides a
valuable alternative for the majority of the investigated substrates.
Unfortunately, preliminary attempts to catalyze the intermolecular
carbonyl-olefin metathesis between benzaldehyde and acyclic
alkenes remained unsuccessful.
Figure 2. Self-assembly of building block 1 into hexameric host I.
As a model reaction, the carbonyl-olefin metathesis of -ketoester
2 (Table 1) was investigated, based on previous studies by
Schindler and coworkers.[6] In initial experiments, substrate 2 was
treated with 10 mol% of hexamer I and 10 mol% of HCl in
chloroform at 50 °C. GC analysis indicated complete conversion
of the starting material after 2 days. Subsequent isolation of
product species 3 confirmed the capability of the hexamer I/HCl
system to catalyze the carbonyl-olefin metathesis. Importantly,
successful conversion was only observed in the presence of both
catalytic components (see below). Based on an optimization of
the HCl content (Supporting Information (SI) chapter 5), a
combination of 10 mol% of hexamer I and 5 mol% of HCl (Table
1, entry 1) was chosen as the standard condition for the
subsequent investigations. In the absence of HCl, no conversion
of substrate 2 was observed under otherwise identical conditions
(Table 1, entry 2). Furthermore, no conversion of substrate 2 was
observed in the absence of hexamer I (Table 1, entry 3). This
demonstrates that
a
synergistic interplay between the
supramolecular host and the Brønsted acid is required for
catalytic activity.
Next, a series of control experiments were performed, which
confirmed that the reaction only takes place inside the cavity of
hexamer I (SI chapter 8). For example, when the cavity was
blocked by addition of a strong binding ammonium guest, the
conversion of substrate 2 dropped to 6% after 4 days.
Additionally, when a mixture of differently sized -ketoesters was
subjected to the reaction conditions, a significantly faster
conversion of the smaller substrate was detected, due to its more
efficient encapsulation. In contrast, when the same experiment
was performed with FeCl3, no size selectivity was observed.
Table 1. Control experiments using the optimized conditions.
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10.1002/anie.201712141
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Table 2. Scope of the hexamer I/HCl-catalyzed carbonyl-olefin metathesis.[a]
29 (Scheme 1) (SI chapter 7). It was expected that, in the case of
a stepwise mechanism, the formation of a six-membered cyclic
ether should be kinetically favored over the oxetane formation.
Indeed, when probe 29 was subjected to the standard reaction
conditions, heterocycle 31 was isolated as the sole reaction
product, providing strong evidence for a stepwise oxetane
formation, also favored by Li and coworkers. It is noteworthy that
the strong evidence for a concerted, asynchronous oxetane
formation, provided by the Schindler group, was based on studies
with 1,3-dicarbonyl compounds. In contrast, the herein presented
evidence and the evidence by the Li group were obtained from
,-unsaturated aryl ketones. It appears likely that the mechanism
of the oxetane formation depends on the employed substrate
type. The reported influence of the olefin substitution pattern on
the mechanism of the oxetane fragmentation step further
corroborates this hypothesis.[9] This assumption might also
explain the improved yields for substrates 15, 17 and 19 with
hexamer I/HCl, as the aromatic cavity has been demonstrated to
provide an excellent medium for cationic cascade reactions.[13-14,
16]
Scheme 1. Evidence for a stepwise oxetane formation.
In summary, it has been demonstrated that the presence of a
supramolecular host enables for the first time a general protocol
for Brønsted acid-catalyzed carbonyl-olefin metathesis. The
control experiments performed clearly show that the
supramolecular host and the Brønsted acid work in a synergistic
fashion to catalyze the metathesis reaction and that the reaction
proceeds inside the cavity of the host structure. The developed
catalytic system provides comparable or even better yields than
the current Lewis acid benchmark catalyst. Superior performance
is especially observed with substrates bearing Lewis basic
functionalities and ,-unsaturated aryl ketones. Additionally, a
mechanistic probe was shown to undergo stepwise oxetane
formation under the optimized conditions. These results further
highlight the increasing applicability of supramolecular catalysts
for challenging organic transformations.
Acknowledgements
This work was supported by funding from the European Research
Council Horizon 2020 Programme [ERC Starting Grant 714620-
TERPENECAT], the Swiss National Science Foundation as part
of the NCCR Molecular Systems Engineering and the Bayerische
Akademie der Wissenschaften (Junges Kolleg).
Keywords: metathesis • host-guest systems • supramolecular
catalysis • self-assembly •  interactions
Intrigued by the seemingly contradictory reports on the
mechanism of the oxetane formation by the groups of Schindler
and Li,[8-9] we decided to investigate the mechanism that applies
to the hexamer I/HCl system, by employing the mechanistic probe
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Entry for the Table of Contents
COMMUNICATION
Lorenzo Catti and Konrad Tiefenbacher*
Page No. – Page No.
Brønsted Acid-Catalyzed Carbonyl-
Olefin Metathesis inside a Self-
Assembled Supramolecular Host
Metathesis inside a host: A supramolecular host enables a general protocol for Brønsted acid-catalyzed carbonyl-olefin metathesis
for the first time. A synergistic interplay between the host and the Brønsted acid is required for catalytic activity. The developed system
provides comparable or even better yields than the current Lewis acid benchmark catalyst. A mechanistic study furthermore indicates
a stepwise oxetane formation for some of the employed substrates.
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