Catalytic Electrophilic C-H Silylation of Pyridines Enabled by Temporary Dearomatization

Article abstract of DOI:10.1002/anie.201508181

A C-H silylation of pyridines that seemingly proceeds through electrophilic aromatic substitution (S_EAr) is reported. Reactions of 2- and 3-substituted pyridines with hydrosilanes in the presence of a catalyst that splits the Si-H bond into a hydride and a silicon electrophile yield the corresponding 5-silylated pyridines. This formal silylation of an aromatic C-H bond is the result of a three-step sequence, consisting of a pyridine hydrosilylation, a dehydrogenative C-H silylation of the intermediate enamine, and a 1,4-dihydropyridine retro-hydrosilylation. The key intermediates were detected by ¹H NMR spectroscopy and prepared through the individual steps. This complex interplay of electrophilic silylation, hydride transfer, and proton abstraction is promoted by a single catalyst.

Full text of DOI:10.1002/anie.201508181

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201508181
German Edition: DOI: 10.1002/ange.201508181
CÀH Activation
À
Catalytic Electrophilic C H Silylation of Pyridines Enabled by
Temporary Dearomatization
Simon Wübbolt and Martin Oestreich*
[
7]
Abstract: A CÀH silylation of pyridines that seemingly
Our strategy merges 1,4-hydrosilylation of pyridines
(I!II), dehydrogenative C-silylation of N-silylated en-
amines
proceeds through electrophilic aromatic substitution (S Ar)
E
[
8,9]
is reported. Reactions of 2- and 3-substituted pyridines with
(II!III), and retro-hydrosilylation of 1,4-dihydro-
[10]
hydrosilanes in the presence of a catalyst that splits the SiÀH
pyridines (III!IV) into a one-pot procedure (Scheme 1).
bond into a hydride and a silicon electrophile yield the
corresponding 5-silylated pyridines. This formal silylation of
an aromatic CÀH bond is the result of a three-step sequence,
A simplified description of this three-step sequence is that the
consisting of a pyridine hydrosilylation, a dehydrogenative
CÀH silylation of the intermediate enamine, and a 1,4-dihy-
dropyridine retro-hydrosilylation. The key intermediates were
1
detected by H NMR spectroscopy and prepared through the
individual steps. This complex interplay of electrophilic
silylation, hydride transfer, and proton abstraction is promoted
by a single catalyst.
C
atalytic processes that employ hydrosilanes to transform
an unactivated CÀH bond into a synthetically valuable CÀSi
[1]
bond are presently garnering tremendous attention. The
current state of the art includes broadly applicable transition-
[
2]
metal-catalyzed CÀH silylations and a rather unorthodox
[
3]
CÀSi bond formation promoted by KOtBu, as well as
[4]
Friedel–Crafts-type approaches. Something that these and
[
5]
other methods, except for a few recent examples, share is
that pyridines do not participate readily. Instead, the pyridin-
Scheme 1. Strategy for an electrophilic CÀH silylation of pyridines that
does not follow an S Ar reaction at the pyridine nucleus. Si=triorgano-
E
2
-yl donor in 1 usually acts as a robust directing group in
[6]
silyl.
transition-metal-catalyzed CÀH silylation (Figure 1, left).
We disclose herein a counterintuitive solution to the problem
of pyridine CÀH silylation that even leaves the phenyl group
[
10]
in 1 intact (Figure 1, right).
reversible 1,4-hydrosilylation is the tool to break (step 1)
and reestablish (step 3) the aromaticity of the pyridine
I.
[11,14,15]
The actual CÀH silylation event (step 2) happens at
the stage of the dearomatized pyridine, i.e., the 1,4-dihydro-
pyridine II. All steps are mediated by the same catalyst, the
[16]
tethered RuÀS complex V (2; Scheme 2). The RuÀS bond
in V cleaves the SiÀH bond of hydrosilanes into a metal
[
17]
hydride and a sulfur-stabilized silicon cation (V!VI).
[
7]
[8]
Lewis-basic substrates such as pyridines I or enamines II
abstract the silicon electrophile from VI to form the RuÀH
Figure 1. CÀH bonds in 2-phenylpyridine (1) addressed by conven-
tional (left) and unconventional (right) CÀH silylation.
complex VII (VI!VII). The dichotomous reactivity of VII is
critical for the success of the present undertaking: it reacts
either as a hydride donor or a proton acceptor, thereby
enabling both hydrosilylations (as step 1; Scheme 1) and
dehydrogenative couplings (as step 2; Scheme 1). When these
components all act in concert, the one-pot transformation of
pyridines I into 5-silylated pyridines IV outlined in Scheme 1
will be achievable.
[
*] S. Wübbolt, Prof. Dr. M. Oestreich
Institut für Chemie, Technische Universität Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
[
7,8]
The individual reactions
proceed at room temperature
Homepage: http://www.organometallics.tu-berlin.de
but the desired sequence then stops at the stage of the 1,4-
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201508181.
dihydropyridine. We therefore tested pyridine (3) as well as
[
7]
selected 3- and 2-substituted congeners (4–6 and 1; Figure 2)
1
5876
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Angewandte
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[a]
Table 1: Catalyst and hydrosilane identification.
[b]
Entry
Catalyst
Hydrosilane
Conv. [%]
1
2
3
4
5
6
2a (R=Et)
2b (R=iPr)
2c (R=4-FC H )
2b (R=iPr)
2b (R=iPr)
2b (R=iPr)
Me PhSiH
33
82
47
2
Me PhSiH
2
Me PhSiH
6
4
2
[c]
EtMe SiH
3
2
MePh SiH
no reaction
no reaction
2
Et SiH
3
Scheme 2. Cooperative SiÀH bond activation and silicon cation trans-
[a] Reactions were performed on a 0.14 mmol scale. [b] Determined by
GLC analysis with reference to the starting material. [c] Desired pyridine
not detected by GLC–MS analysis.
F
4
À
fer (counteranion BAr omitted for clarity, top), and the tethered
F
RuÀS complexes 2 tested as catalysts (bottom). Ar =3,5-bis(trifluoro-
methyl)phenyl.
Figure 2. Performance of model compounds tested in the initial
screening.
[7]
[8]
at 808C with catalysts 2a and 2b. The reaction of 4-
substituted pyridines was messy (data not shown). It must be
noted that 2-substituted pyridines 6 and 1 had not been
[
7]
amenable to room-temperature hydrosilylation. A broad
screening of reaction parameters applied to those pyridines
revealed that parent 3 yields complex mixtures while the
other model compounds showed formation of the desired 5-
silylated pyridine derivative (Figure 2). The reactions of
pyridine 1 with a phenyl group at C2 were fairly clean, and
we continued with 1 to further optimize the method. Also,
[9]
unlike the work of Chang, Park, and co-workers, quinoline
yielded an intractable mixture.
Another result of this preliminary screening was that the
use of any solvent, typically non-donating solvents such as
Scheme 3. 5-Selective CÀH silylation of 2- and 3-substituted pyridines.
[a] Reactions were performed on a 0.14 mmol scale. Yields of isolated
products after purification by flash chromatography on silica gel.
(
chlorinated) hydrocarbons, thwarts conversion. As a conse-
quence, reactions were run in excess hydrosilane (10 equiv).
Under these boundary conditions, we tested catalysts 2a–c in
[
[
b] Isolated from a complex mixture, still containing impurities.
c] Reaction was performed on a 0.14 mmol scale with 5.0 equiv of the
the CÀH silylation of 1 with Me PhSiH (1!7; Table 1,
2
hydrosilane at 808C for 3 h.
entries 1–3). Complex 2b, which was previously used in
[8]
enamine dehydrogenative coupling, was superior to 2a from
[
7]
[18]
the pyridine hydrosilylation; 2c, which has an electron-
deficient phosphine ligand, was also less effective. Other
triorganosilanes such as EtMe SiH, MePh SiH, and Et SiH
moderate yields in this and subsequent reactions, we were not
able to identify any major byproducts. We next probed the
scope with respect to pyridines substituted with electronically
different aryl groups in the 2-position (8–12; Scheme 3). Both
electron-donating and electron-withdrawing groups were
tolerated. Compound 10, which has a difluorinated aryl
group, afforded an excellent 86% yield, but a dimethylamino
group in the 4-position of the aryl group led to a diminished
2
2
3
did not participate in this multistep sequence (Table 1,
entries 4–6).
The optimized reaction setup afforded the 5-silylated 2-
phenylpyridine 7 in 59% yield of isolated product. We
consider this a decent result, keeping in mind that the reaction
passes through several reactive intermediates. Despite the
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yield of 24%. Alkylation at C2 of the pyridine was also
accepted although yields were substantially lower (6 and 13;
Scheme 3). Except for 3-picoline (4; Scheme 3), none of the 3-
required in the final step (24!21), which is consistent with
earlier findings by Nikonov and co-workers.
[10]
We present herein a one-pot transformation that is usually
[7]
substituted pyridines reacted cleanly, usually furnishing low
considered virtually impossible: a formal S Ar of pyridines
E
yields (e.g., 15% for 5 to afford 22, data not shown). The CÀH
with electrophilic silicon. The trick is to temporarily break the
aromaticity and exploit the nucleophilicity of the enamine
silylation of 4 was successful, giving 65% yield of isolated
product.
[11,14,15]
intermediate.
The strategy hinges on the reversible 1,4-
[7,10]
We were also able to detect the assumed key intermedi-
hydrosilylation of pyridines,
and we discovered that the
ates, 1,4-dihydropyridines 23 and 24 when monitoring the
same catalyst also promotes dehydrogenative silylation of the
nucleophilic enamine carbon atom. The net result of this
three-step sequence is a meta-selective CÀH silylation of
mainly 2-substituted pyridines that would otherwise be
difficult to achieve in a single synthetic operation.
1
[8]
reaction of 4 and Me PhSiH by H NMR spectroscopy (4!
2
2
3!24; Scheme 4). In the presence of excess Me PhSiH,
2
Acknowledgements
This research was supported by the Deutsche Forschungsge-
meinschaft (Oe 249/10-1). M.O. is indebted to the Einstein
Foundation (Berlin) for an endowed professorship. We thank
Dr. Hendrik F. T. Klare (TU Berlin) for insightful discussions.
Keywords: CÀH activation · electrophilic substitution ·
hydrosilylation · N-heterocycles · SiÀH bond activation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15876–15879
Angew. Chem. 2015, 127, 16103–16106
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2
pyridine 4 fully converts into 1,4-dihydropyridine 23 within
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[
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10]
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[
7]
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1
35, 13149 – 13161.
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[
[
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[
8]
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air alone leads to rearomatization. The catalyst is thus
(1.0 equiv) and hydrosilanes (1.0 equiv). Excellent yields of the
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1
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Angew. Chem. Int. Ed. 2015, 54, 15876 –15879

Angewandte
Chemie
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[
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[
12]
dines
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[13]
silylated enamine.
Elimination and desilylation eventually
Received: September 1, 2015
Revised: October 15, 2015
Published online: November 17, 2015
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Angew. Chem. Int. Ed. 2015, 54, 15876 –15879
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