Iron-Catalyzed Ring-Closing C?O/C?O Metathesis of Aliphatic Ethers

Article abstract of DOI:10.1002/anie.201802563

Among all metathesis reactions known to date in organic chemistry, the metathesis of multiple bonds such as alkenes and alkynes has evolved into one of the most powerful methods to construct molecular complexity. In contrast, metathesis reactions involving single bonds are scarce and far less developed, particularly in the context of synthetically valuable ring-closing reactions. Herein, we report an iron-catalyzed ring-closing metathesis of aliphatic ethers for the synthesis of substituted tetrahydropyrans and tetrahydrofurans, as well as morpholines and polycyclic ethers. This transformation is enabled by a simple iron catalyst and likely proceeds via cyclic oxonium intermediates.

Full text of DOI:10.1002/anie.201802563

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Title: Iron-Catalyzed Ring-Closing C-O/C-O Metathesis of Aliphatic
Ethers
Authors: Tobias Biberger, Szabolcs Makai, Zhong Lian, and Bill
Morandi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802563
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Iron-Catalyzed Ring-Closing C–O/C–O Metathesis of Aliphatic
Ethers
Tobias Biberger, Szabolcs Makai, Zhong Lian, Bill Morandi*[a]
Dedicated to Professor Christoph A. Schalley on the occasion of his 50th birthday
Abstract: Among all metathesis reactions known to date in organic
chemistry, the metathesis of multiple bonds such as alkenes and
alkynes has evolved into one of the most powerful methods to
construct molecular complexity. In contrast, metathesis reactions
involving single bonds are scarce and far less developed, particularly
in the context of synthetically valuable ring-closing reactions. Herein,
we report an iron-catalyzed ring-closing metathesis of aliphatic
ethers for the synthesis of substituted tetrahydropyrans and
tetrahydrofurans, as well as morpholines and polycylic ethers. This
transformation is enabled by a simple iron catalyst and likely
proceeds through cyclic oxonium intermediates.
Following our continuous effort to develop new catalytic
isodesmic reactions,[9] we were interested to investigate whether
two C(sp3)–O bonds could engage in a ring-closing metathesis
manifold. Due to the ubiquity of aliphatic cyclic ethers, such as
tetrahydrofurans and tetrahydropyrans, in all fields of chemistry,
[10]
we thought that the synthesis of these substrates through a
metathesis strategy would efficiently complement traditional
methods[11,12] for ether synthesis. In particular, the ability to
engage two identical functionalities[13] (i.e. two ROR’ groups) in
this reaction would reduce the overall number of synthetic steps
when compared to traditional methods, such as the Williamson
ether synthesis,[14] which require the separate preinstallation of
two distinct functional groups (i.e. C–Br and C–O-) prior to the
etherification step.
Metathesis reactions involving multiple bonds are arguably
among the most interesting reactions in organic synthesis.[1] In
particular, ring-closing alkene[2] and alkyne[3] metathesis have
become powerful synthetic tools for the synthesis of small,
medium and large rings. Researchers have recently been trying
to translate the power of ring-closing metathesis reactions to
other types of multiple bonds. Most notably, the Schindler and Li
groups have reported catalytic ring-closing metathesis reactions
between alkenes and carbonyls under iron catalysis.[4] This new
reaction has already been applied in the synthesis of conjugated
materials and unsaturated heterocycles.
Herein, we report an iron-catalyzed ring-closing C–O/C–O bond
metathesis reaction for the synthesis of tetrahydrofurans,
tetrahydropyrans and morpholines from simple aliphatic diethers.
By contrast, less effort has been dedicated to the development
of catalytic single-bond metathesis reactions. This trend may
originate from the lower reactivity of single bonds when
compared to multiple bonds, a feature that complicates the
design of suitable bond activation mechanisms in catalytic
processes. Only a few examples of C–X bond metathesis
reactions have been published, and include amide bond
metathesis,[5] carbon-sulfur and carbon-phosphorus bond
metathesis[6] and carbon-silicon bond metathesis.[7] Notably, a
significant amount of these reactions involve the cleavage of
C(sp2)–X bonds through reversible oxidative addition,
a
mechanism which is not easily extendable to C(sp3)–X bonds
because of competing β-hydride elimination of the alkyl–M
intermediates and higher barriers for oxidative addition.[8]
Moreover, there is no example of a catalytic ring-closing
metathesis reaction involving two single C(sp3)–X bonds, despite
the potential of such reactions to enable a rapid access to
saturated carbo- and heterocyclic products that are key
intermediates in organic synthesis.
Scheme 1. Context of the work.
Inspired by our previous results in aromatic thioether
metathesis,[6] we started our investigation with the evaluation of
a wide range of Pd and Ni catalysts for the ring-closing
metathesis of 1,5-dimethoxypentane (1). However, both the
challenges involved with the oxidative addition of a very strong
bond, C(sp3)–O, and the known propensity of alkyl–M
intermediates to undergo β-hydride elimination, forced us to
reevaluate our design after unsuccessful preliminary results. We
reasoned that Lewis acid catalysis, which had been successfully
used by Schindler and Li in carbonyl-olefin metathesis,[4] might
facilitate an ether bond metathesis reaction proceeding through
the intramolecular attack of an ether group onto a Lewis acid
activated ether group. The oxonium intermediate generated from
[a]
Tobias Biberger, Szabolcs Makai, Dr. Zhong Lian, Dr. Bill Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Email: morandi@kofo.mpg.de
Supporting information for this article is given via a link at the end of
the document.
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this process may then collapse with the M–OR species to
regenerate the active catalyst and the two products. This
rationale is indirectly supported by a report from Enthaler in
which the authors realized the depolymerization of poly-THF
under Fe-catalysis through the continuous removal of the
monomeric product, THF, by distillation.[15]
15) in good to excellent yields. More sterically demanding
substrates with a gem-dimethyl group at the 3-position (12-15)
were converted in good yields into the corresponding products,
when the catalyst loading was increased to 50 mol%, suggesting
that the catalyst is somewhat sensitive to steric bulk. When the
two methoxyethers were appended to a carbocyclic ring system,
we observed a particularly fast reaction with clean formation of
the corresponding polycyclic tetrahydrofuran products (16-17).
Moreover, the reaction could be extended to spirocycle
synthesis (18), showcasing the potential of this method to rapidly
generate unusual heterocyclic architecture that are of potential
interest to drug discovery. Benzylic and secondary ethers, as
well as substrates that contained alkenes or amides (for full
details see SI) were not tolerated in this reaction.
Evaluation of suitable Lewis acids led us to the discovery of a
practical Fe(OTf)3 catalytic system for the cyclization of 1,5-
dimethoxypentane (1) to generate the product (2) in 85% yield.
Generally, MX3 salts with relatively weak coordinating anions
(AlCl3, Sc(OTf)3, FeCl3, FeBr3) performed well in this reaction,
clearly indicating that the reaction indeed proceeds via Lewis
acid catalysis. However, no other Lewis acid matched the
activity of the Fe(OTf)3 catalyst. A screening of various solvents
revealed that more coordinating solvents (acetonitrile,
chlorinated solvents) were detrimental to the reaction. A control
reaction using triflic acid, which could possibly be formed under
the reaction conditions in the presence of water traces, only led
to low conversion to the product, confirming that Lewis acid
catalysis is most likely responsible for the high reactivity
observed. Further control reactions confirmed that a temperature
of 100 °C and a concentration of 0.45 M are best for this
transformation.
Table 2. Scope of the iron-catalyzed ring-closing metathesis.[a]
Table 1. Reaction Optimization.[a]
Entry
Deviation from Standard Conditions
none
Yield of 2[b]
1
2
85
78
AlCl3 instead of Fe(OTf)3
3
4
5
6
7
8
9
Sc(OTf)3 instead of Fe(OTf)3
Other Lewis acids[c]
67
11-72
28
TfOH instead of Fe(OTf)3
Acetonitrile, DCM, benzene instead of hexane
80 °C instead of 100 °C
11-71
72
0.22 M instead of 0.45 M
69
No Lewis acid
0
[a] see SI for detailed conditions. [b] GC-yields in % using dodecane as an
internal standard. [c] B(C6F5)3, FeBr3, AlMe2Cl, FeCl3.
With optimal conditions for the C–O/C–O metathesis in hand, we
explored the substrate scope of this transformation (Table 2).
Generally, five- as well as six-membered rings can be accessed
using our new single-bond metathesis reaction by simple
variation of the chain-length of the aliphatic ethers. Notably,
totally unbiased substrates can also cyclize efficiently under
these reaction conditions. This result stands in contrast to many
other cyclization reactions that require a Thorpe-Ingold effect to
efficiently generate cyclized products, often limiting the substrate
scope.[16] Aromatic rings bearing various functional groups
(arylfluoride, -chloride, -bromide, -methoxy, -methyl,
-
trifluoromethyl) that offer a handle for further functionalization
were well tolerated and provided the corresponding products (9-
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[a] Yields of isolated products. [b] 20 mol%, 18 h. [c] 20 mol%, 48 h. [d] 50
mol%, 48 h.
Dioxanes and morpholines are among the most commonly
encountered heterocycles in drug design. We were thus
interested to test whether these saturated heterocycles could be
accessed with our methodology through the cyclization of the
corresponding heteroatom-rich starting materials. Excitingly,
while the strong coordinating ability of those substrates could
have been deleterious to the reaction, we obtained the desired
products in high yields (Scheme 2). 1,4-dioxane (22) as well as
nosyl- and tosyl-protected morpholines (19, 20) could thus be
accessed using our methodology.
Scheme 3. Mechanistic experiments.
Our working model for the initial design of this reaction involved
the intramolecular attack of a second ether onto a Lewis acid
coordinated ether group through an intramolecular nucleophilic
attack to generate a key oxonium intermediate along with a
metal alkoxide. Several experiments support this mechanistic
picture (Scheme 4). First, an independently generated cyclic
oxonium intermediate (26) did react with an “Fe–OMe” (27)
species, which was generated in situ by mixing Fe(OTf)3 with
equimolar NaOMe, to form the THP (2) product along with
dimethyl ether (3). Second, a crossover experiment using two
substrates (1, 28) having different oxygen substituents, Me and
Pr, resulted in the formation of MeOPr (29) as the major by-
Scheme 2. Applying ring-closing metathesis to morpholine and dioxane
synthesis.
product,
a
result that supports
a
bimolecular reaction
We next aimed to detect and possibly understand the role of the
dimethyl ether that should be formed as a by-product under the
reaction conditions (Scheme 3). First, we ran the model reaction
on a 1.7 mmol scale in a pressure-vial equipped with a septum
cap. Using a gastight syringe, the gases present in the head
space were subsequently analyzed by GC-MS and the presence
of dimethyl ether (3) was unambiguously confirmed by
comparison with two independent library spectra (for more
details see SI). Next, we wondered if the formation of gaseous
dimethyl ether (3) as a by-product was the determining factor in
driving forward the equilibrium of this potentially reversible
reaction. This was ruled out by a set of experiments which,
despite involving the formation of heavier, non-volatile ether by-
products (23, 24) instead of dimethyl ether (3), led to identical
conversions and yields of the product (2). This result, together
with the absence of reactivity between THP (2) and dibutyl ether
(24), suggests that the formation of THP (2) is irreversible under
these reaction conditions.
mechanism. The intermediacy of a cyclic oxonium species is
also indirectly supported by a surprising result obtained when
the reaction was performed with stoichiometric AlCl3 instead of
catalytic Fe(OTf)3. In this experiment, 1-chloropropane (32) was
obtained almost exclusively as a by-product instead of dipropyl
ether (23), a result probably best explained by selective chloride
delivery from a tetracoordinated [AlCl3(OPr)]– (33) species onto
the cyclic oxonium intermediate (31).
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for the development of new metathesis reactions involving inert
C(sp3)–X bonds.
Acknowledgements
We acknowledge the Max-Planck-Society and the Max-Planck-
Institut für Kohlenforschung for continuous support of our
research program. Financial support from the European
Research Council under the European Union’s Horizon 2020
research and innovation program (grant agreement No 757608
ShuttleCat) is gratefully acknowledged. We thank Prof. Dr.
Benjamin List for sharing analytical equipment and our analytical
departments (X-Ray, MS and GC) for excellent support.
Keywords: metathesis, iron catalysis, ethers, tetrahydropyrans,
tetrahydrofurans, morpholines
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In conclusion, we have presented the first synthetically relevant
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substituted tetrahydrofuran and tetrahydropyran derivatives in an
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intermediates. Overall, our reaction design provides a blueprint
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