Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles

Article abstract of DOI:10.1002/anie.201804124

We report a method to convert readily available silylated arenes into silylated saturated carbo- and heterocycles by arene hydrogenation. The scope includes alkoxy- and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find application in organic synthesis, materials science, and pharmaceutical, agrochemical, and fragrance research. However, silylated saturated (hetero-) cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amount of the silica gel additive. This silica effect also enables a significant improvement of a previously disclosed method for the hydrogenation of highly fluorinated arenes (e.g., to all-cis-C₆H₆F₆).

Full text of DOI:10.1002/anie.201804124

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Accepted Article
Title: Silylarene hydrogenation - a strategic approach enabling direct
access to versatile silylated saturated carbo- and heterocycles
Authors: Mario Wiesenfeldt, Tobias Knecht, Christoph Schlepphorst,
and Frank Glorius
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201804124
Angew. Chem. 10.1002/ange.201804124
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10.1002/anie.201804124
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Silylarene hydrogenation – a strategic approach enabling direct
access to versatile silylated saturated carbo- and heterocycles
Mario P. Wiesenfeldt, Tobias Knecht, Christoph Schlepphorst, Frank Glorius[a]*
Abstract: We report a method to convert readily available silylated
arenes into silylated saturated carbo- and heterocycles by arene
hydrogenation. The scope includes alkoxy and halosilyl substituents.
Silyl groups can be derivatized into a plethora of functionalities and
find application in organic synthesis, materials science,
pharmaceutical, agrochemical, and fragrance research. Yet,
silylated saturated (hetero- ) cycles are difficult to access with current
technologies. The yield of the hydrogenation depends on the amount
of the silica gel additive. This silica effect also enables a significant
improvement of the previously disclosed protocol for the
hydrogenation of highly fluorinated arenes (e.g. to all-cis-C6H6F6).
Arene hydrogenation provides a direct way to connect readily
accessible two-dimensional (2D) aromatic with underexplored
3D aliphatic chemical space (Figure 1, A). As such, it holds
strategic value for applied sciences e.g. medicinal chemistry.[1]
A
major barrier for synthetic applications of this transformation[2] is
the limited tolerance of functional group (FG) substituents
directly attached to the reactive aromatic ring. Such substituents
tend to influence the activity so that reaction inhibition and
defunctionalization can occur. E.g. silylated arenes can be
unstable to electrophiles and nucleophiles. The β-silicon effect
enables a facile electrophilic attack at the arene and the
accessibility of hypervalent species enables a facile nucleophilic
attack at silicon. Both pathways affect a net desilylation and their
use for rhodium-catalyzed reactions (in absence of (fluoride)
activators) is known.[3] Furthermore, alkoxy and halosilyl groups
are prone to nucleophilic cleavage of the Si–X bond and the large
steric demand of silicon substituents can hinder productive
coordination to the catalyst.[4] A general protocol that overcomes
those challenges would be of interest as (alkyl)silyl groups are
widely employed in organic synthesis[5] as reagents[6] or for
elaboration of the structure by a myriad of transformations such
as Hiyama couplings, Fleming-Tamao oxidations, or Brook
rearrangements.[7] Alkoxy and halosilyl groups are used in
materials science e.g. for the preparation of polymers and
inorganic–organic hybrid materials.[8] Finally, silicon can serve as
carbon isoster, thus prompting interest in the preparation of sila-
analogues in the pharmaceutical, agrochemical,[9] and
Figure 1. a) Arene hydrogenation connects 2D aromatic chemical space with
underexplored 3D aliphatic chemical space. b) Our protocol enables direct
access to silylated saturated carbo- and heterocycles including alkoxy and
halosilyl substituents. c) Synthetic utility of alkoxy or halosilyl groups.
fragrance[10] research. However, no general method for the
synthesis of silylated carbo- or heterocycles is known. Olefin
hydrosilylation is complicated by a difficult control over regio- and
diastereoselectivity for such 1,2-disubstituted alkenes[11] and the
trapping of (cyclo- ) alkyl-Grignard or lithium reagents with silyl
electrophiles has a limited FG-tolerance. While this problem has
been elegantly addressed by Fu, Oestreich, and Watson,[12]
a
diastereoselective method to access substituted silylated carbo-
or heterocycles and particularly alkoxy and halosilyl groups has
remained out of reach. A logical solution to this challenge is
arene hydrogenation as a plethora of silylated arenes are
commercially available or can easily be synthesized by
established methods.[13] To date, the hydrogenation of silylated
arenes has only been conducted for a handful of very simple
[a]
M. P. Wiesenfeldt, T. Knecht, C. Schlepphorst, F. Glorius*
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstraße 40, 48149 Münster (Germany)
glorius@uni-muenster.de
Supporting information for this article is given via a link at the end of
the document.
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Figure 2. Scope of the hydrogenation of silylated arenes. Isolated yields. D.r. values were determined by GC-MS prior to isolation. For details, see SI. [a] 4 Å MS
instead of silica gel. [b] 19F NMR yield with 1,3,5-trifluorobenzene as internal standard. [c] Reaction in methanol. Protection with trifluoroacetic anhydride after the
reaction.
substrates.[14] Herein, we provide the first comprehensive
synthetic study, which enables general access to silylated
saturated carbo- and heterocycles including for the first time the
synthetically most valuable alkoxy and halosilyl substituents and
silylated heterocycles (Figure 1 B, C).
significant amounts of desilylated side products were only
detected under conditions in which the hydrogenation reaction
was inefficient (e.g. Table S3, entry 4).
Next, the scope was explored under the optimized conditions
(Figure 2). We began the systematic evaluation by the variation
of the silyl group.[17] No significant influence of the steric size (3a–
d) was observed. In all cases, the products were obtained in high
yields and d.r. values. The hydrogenation of ortho-substituted
substrate 2e provided the product as single diastereomer.
Reactive alkoxy- (2g–i) and halosilyl substituents (2j–l) were well-
tolerated. Next, the combination of silyl substituents with other
Based on our recent work on the hydrogenation of fluorinated
arenes[2f] we anticipated Zeng’s complex (1)[15] to be perfectly
suited for the development of a broadly applicable and easily
reproducible protocol.[16] The optimization was conducted using
aryltrimethylsilane 2a (Table S1–S5). Notably, a higher d.r. was
observed when exchanging the 4 Å MS additive with silica gel and
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FGs directly attached to the aromatic ring was tested. Valuable
FGs such as BPin (2m–o), Boc-protected amine (2p), ester (2q,
z), and TBS-protected alcohol (2r), which offer sites for orthogonal
functionalization of the products, were well-tolerated. Electron-
donating methoxy (2s) as well as electron-withdrawing
trifluoromethyl substituents (2t, u), and fluorine (2v, y) could be
combined with a silyl substituent at the aromatic ring. Even alkyl
chlorides were tolerated under the reaction conditions (2w). We
proceeded to evaluate fused arenes and heteroarenes. 1-
Trimethoxysilyl-naphthalene (2aa) was fully reduced in good yield.
The hydrogenation of furan derivative 2ab gave the resulting
product as single diastereomer in excellent yield. Various silylated
saturated N-heterocycles (3ac–ae) could be synthesized with our
method. 3-TES-substituted pyridine 2af could be hydrogenated
after switching the solvent to methanol. In many cases, the
separation of the diastereomers was achieved by column
chromatography. Scale-up to 5 mmol was performed for two
representative examples (3a, 3ab). The cis-selectivity was proven
for 3e (NOE, Figure S1) and 3p (x-ray).[18]
Figure 4. Application of the silica effect for the hydrogenation of highly
fluorinated arenes. Isolated yields. All d.r. values were >20:1 (19F NMR).
Finally, we were intrigued by the observed increase of the
yield with greater amounts of silica gel and questioned whether
this effect might also enable further optimization of our previously
published protocol for the hydrogenation of fluorinated arenes.
While this protocol facilitated the hydrogenation of a broad scope
of fluorinated arenes and heteroarenes in high yields, highly
fluorinated arenes were reduced in moderate yields only (even
when using silica gel as additive).[2f] Herein, we discovered that a
simple threefold increase of the amount of silica gel enabled
complete conversion of hexafluorobenzene (5a, Table S7). We
assume a high surface area of the (insoluble) additive to be crucial
for an efficient reaction. The corresponding all-cis-C6H6F6 (6a)
could be isolated in an excellent yield as a single diastereomer
and the generality of this effect was shown (6b, c) Notably, the
new conditions allowed for a significantly more concentrated
setup (0.5 M vs 0.07 M, previously), and thus enabled the scale-
up to a 20 mmol scale using standard autoclave equipment. The
access to multi-gram quantities of all-cis-multifluorinated
cycloalkanes is now convenient.
In conclusion, we disclose a general protocol for the
hydrogenation of widely accessible silylated arenes using a
rhodium–CAAC catalyst. This method provides direct access to
sought-after 3D motifs and was applied to the synthesis of a
silylated analogue of esperisone and sila-woody acetate, the sila
analogue of a known odorant. The use of this method for the
synthesis of tailor-made building blocks for materials science,
pharmaceutical and agrochemical research, and the development
of fragrances is possible. Finally, the application of the silica effect
(increased yields upon using greater amounts of the silica gel
additive) to the previously published hydrogenation of highly
fluorinated arenes gave significantly enhanced yields.
Figure 3. Applications.
To demonstrate that the silylated building blocks can be
incorporated into complex scaffolds, a silylated analogue of the
muscle relaxant esperisone (4) was prepared by a Mannich
reaction of the deprotected, silylated piperidine 3af (Figure 3, A).
No desilylation was observed during the base-mediated
deprotection or the acid-catalyzed Mannich reaction. The addition
of silyl-groups to lead compounds is a promising strategy to
improve the pharmacokinetic properties.[9] To further prove the
utility, we conducted the silicon switch (i.e. exchanging carbon
with silicon) for the odorant “woody acetate”. Notably, the cis-
isomer of the commercial fragrance is responsible for the more
intense smell.[19] The synthesis of sila-analogues of known
odorants is actively pursued for the further optimization and for
the elucidation of the structure-activity relationship.[10] Sila-woody
acetate (3ag) was directly accessed by arene hydrogenation. The
obtained product has an intense (pleasant) fruity odor.
Acknowledgements
We thank the Studienstiftung des Deutschen Volkes (M.P.W.)
and the Deutsche Forschungsgemeinschaft (Leibniz Award,
F.G.) for generous financial support. We thank Z. Nairoukh, M.
van Gemmeren, H. Yoon, and L. Pitzer for helpful discussions,
K. Bergander for NMR measurements and C. G. Daniliuc for
crystallographic analysis.
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article: c) A. A. Toutov, W.-B. Liu, K. N. Betz, A. Fedorov, B. M. Stoltz, R.
H. Grubbs, Nature 2015, 518, 80.
Keywords: arene hydrogenation • silicon • 3D chemical space •
cycloalkanes • heterocycles
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Layout 2:
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Mario P. Wiesenfeldt, Tobias Knecht,
Christoph Schlepphorst, Frank Glorius*
Page No. – Page No.
Silylarene hydrogenation – a strategic
approach enabling direct access to
versatile silylated saturated carbo-
and heterocycles
Text for Table of Contents
Any[Si]ng but flat! We report a method to convert readily available silylated arenes into silylated saturated carbo- and heterocycles by arene
hydrogenation. The scope includes alkoxy and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find
application in organic synthesis, materials science, pharmaceutical, agrochemical, and fragrance research. Yet, silylated saturated (hetero- )
cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amount of the silica gel additive. This
silica effect also enables a significant improvement of the previously disclosed protocol for the hydrogenation of highly fluorinated arenes (e.g.
to all-cis-C6H6F6).
This article is protected by copyright. All rights reserved.