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Article
Alkali metal hydroxide–catalyzed C(sp)–H bond silylation
Anton Toutov, Kerry Betz, David Phillip Schuman, Wen-
bo Liu, Alexey Fedorov, Brian M. Stoltz, and Robert H. Grubbs
J. Am. Chem. Soc.
,
Just Accepted Manuscript
• DOI: 10.1021/jacs.6b12114
• Publication Date (Web): 27 Dec 2016
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Alkali metal hydroxide
–
catalyze
d
C(
sp
)
–
H bond silylation
Anton A. Toutov,
1
†
Kerry N. Betz,
1
†
David P. Schuman,
1
Wen
-
Bo Liu,
1
Alexey Fedorov,
1
§
Brian M. Stoltz
1
*
& Robert H. Grubbs
1
*
1
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, 91125, USA
Supporting Information Placeholder
ABSTRACT
:
Disclosed is
a mild, scalable, and chemoselective cat-
alytic cross
-
dehydrogenative C
–
H bond functionalization protocol
for the construction of
C(
sp
)
–
Si bonds in a single step. The scope of
the alkyne and hydrosilane partners is substantial, providing an en-
try point into
various
organosilane building blocks and additionally
enabling the discovery of a number of novel synthetic strategies.
Re-
markably, the
optimal catalyst
s
are
NaOH
and
KOH
.
Introduction.
The catalytic transformation of C
–
H bonds into a variety of usef
ul
functional groups has revolutionized chemical synthesis.
1
However,
the necessity of precious metal catalysts for these transformations
remains a fundamental and longstanding limitation.
2
With the aim
of developing a suite of new methods for powerful, su
stainable, and
cost
-
effective chemical synthesis, we became interested in the use
of Earth
-
abundant metal salts for catalytic cross
-
dehydrogenative
C
–
H bond functionalization reactions.
3
Toward this end, we re-
cently reported the direct C(
sp
2
)
–
H silylation
of aromatic heterocy-
cles with hydrosilanes using catalytic potassium
tert
-
butoxide (KO
t
-
Bu).
4
Building upon this concept, we sought to evaluate alkali metal
salts as catalysts
for
the preparation of alkynylsilanes. These im-
portant building blocks are use
d in the construction of electronically
and
structurally
interesting materials,
5
employed as substrates in
metathesis reactions
6
and cycloadditions,
7
and as precursors to het-
erocycles
8
and polycyclic aromatic frameworks.
9
Moreover, al-
kynylsilane
nucleophiles and cross
-
coupling partners react under
mild conditions
10
and therefore are commonly u
tiliz
ed as versatile
intermediates en route to complex molecules
.
11
Recently,
di
-
tert
-
bu-
tylfluorosilyl alkynes have
been proposed as
a
novel functionality in
the development of next generation radiofluorinated positron emis-
sion tomography (i.e., [
18
F]PET) probes with high in vivo
stability for
non
-
invasive biomedical imaging applications
.
1
2
Strategies for the synthesis of alkynylsilanes have employed
stro
ng bases
(Scheme 1a, Route A)
13
or have relied on stoichio-
metric
14
or catalytic transition metal species
(Scheme 1a, Route B)
15
and typically use various pre
-
activated organosilicon coupling part-
ners such as [Si
–
Cl],
13a,b
;14a,b
[Si
–
I],
15f
[Si
–
NR
2
],
14c
[Si
–
Si],
13d
[Si
–
OTf]
.
15c
Inexpensive and convenient hydrosilanes have been investigated for
C(
sp
)
–
H silylation;
13c
–
e,
g
,
15a,b,d,f
however, the requisite in situ
Si
–
H
bond activation has thus far necessitated additional exogenous ba-
ses,
15b,d
sacrificial hydrogen acceptors
15f
or
external
oxidants,
15a,
d
and
elevated temperatures.
13c,d
,
e
,
15d,f
Moreover, undesired hydrosilylation
of the alkyne can be competitive,
15a,d,f
further complicating catalyst
and reaction des
ign.
Interestingly, highly basi
c
species
such as
MgO,
13c
,
e,
f
KNH
2
/Al2O
3
,
13g
LiAlH4,
13c
,e
n
-
BuLi,
13c
and even alkoxides
13c
have
shown some catalytic activity in the
dehydrocoupling of hy-
drosilanes and alkynes.
However, these reports
are limited to only a
handful of
unfunc
tionalized
examples, the reactions give modest
yields and selectivities, and the chemistry typically
require
s
elevated
temperatures (i.e., 80
–
120 °C)
, severely
lowering the
practical utility
of these strong base
–
catalyzed methods
.
Moreover,
basic function-
alities
such
as
N
-
heterocycles and aliphatic amines have been absent
in all of the aforementioned reports, likely owing to the necessity for
Lewis
-
acidic metal centers and/or electrophilic silicon sources in
Scheme 1.
Approaches to
C
–
H silylation
of alkynes
those reactions. An NHC/NaH
-
catalyzed protocol that is tolerant of
N
-
heterocycles has been reported; however, the use of CF
3
SiMe
3
(Ruppert
–
Prakash reagent) as the silicon source is a disadvantage
from the perspective of
reagent stability, cost, and, in particular,
scope of the silicon partner.
16
Herein, we disclose a mild, efficient, and general catalytic C(
sp
)
–
H
Table 1. Reaction discovery and catalyst evaluation
a
a
Reactions were
conducted on 0.5 mmol scale with 0.5 mL solvent at the prescribed
temperature. DME = 1,2
-
dimethoxyethane. Entries 1
–
5, 8: yields determined by GC
-
FID
analysis with tridecane as an internal standard; entries 6,7: yields of analytically pure
isolated materia
ls. Reaction does not proceed without catalyst.
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bond silylation
of unprecedented scope. The method avoids the fun-
damental limitations of previous strategies, including classical stoi-
chiometric deprotonation and catalytic transition metal
–
catalyzed
approach
es, and uses
readily available
KOH
or
NaOH
as the
optimal
catalyst
s
(
Scheme 1b)
.
Results and Discussion.
We initiated investigations with the silylation of alkyne
1
using
Et
3
SiH under our previously reported KO
t
-
Bu
-
catalyzed C(
sp
2
)
–
H si-
lylation conditions
4a
–
c
and gratifyingly observed alkynylsilane
2a
in
good yield; however,
along with 9% of undesired alkyne migration
product
1
-
iso
(
Scheme 2
, entry 1)
.
17
NaO
t
-
Bu (entry
2
) and LiO
t
-
Bu
(entry
3
)
show poor reactivity, and
pyridine
(
entry 4
)
gives no reac-
tion
.
KOH
is
superior to
KO
t
-
Bu (entry
5
), generating
the
desired
product in 95% yield
with
decreased quantities (3%) of the unde-
sired
1
-
iso
.
Moving from Et
3
SiH to PhMe
2
SiH permits the reaction
to occur at ambient temperature while still maintaining high yield
(entry
6
).
In sharp contrast to our previously
reported heteroarene
C(
sp
2
)
–
H silylation protocol wherein
the catalys
t
was essentially
limited to KO
t
-
Bu,
4a
–
c
the ideal catalysts for the C(
sp
)
–
H silylation
were KOH and NaOH affording
2b
in 89% and 9
3% yield respec-
tively (entries
6
&
7
). By contrast, LiOH (entry
8
) does not catalyze
the reaction.
We next proceeded to evaluate the scope of the hydrosilane part-
ner
(
Scheme 2
) and found that a
lkyl
-
and phenyl
-
substituted hy-
drosilanes of varying steric
demand readily undergo coupling
providing alkynylsilanes
2a
–
d
in high yields
.
The mild conditions of
this reaction
enabl
ed
the facile preparation of alkynylsilanes con-
taining synthetically versatile hydride
-
(
2e
and
2f
), benzyldimethyl
-
(
2g
), triisopropyl
-
(
2h
),
and even triethoxy
-
(
2i
)
and 2
-
dialkylpyridyl
(
2j
and
2k
) moieties in good yield.
Currently, alkynylsilylpyridines
are prepared using stoichiometric organometallic methods, which
intrinsically limits the substrate scope;
18
however,
a
lkynyl dime-
thyl
silylpyridines
such as
2k
can be advanced to di
-
, tri
-
, and tetra
-
substituted olefins by sequential transition metal
-
catalyzed proto-
cols making them valuable C(
sp
)
–
Si functionalities that, given their
remarkable versatility, have to this point been seeming
ly un-
derused.
18
The bulky di
-
tert
-
butylsilane could also be introduced for
the first time by catalytic C
–
H silylation yielding
2f
in excellent yield,
Scheme 2. Scope of the hydrosilane
a,b
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent at the prescribed
temperature.
b
Reactions are run for 48 h, except 24 h for
2c
and
2e
.
providing a point of entry into novel alkynylsilyl [
18
F]
PET
radiophar-
maceutical
moieties.
1
2
Using Me
3
Si
–
SiHMe
2
as a polysilane model
compound and subjecting it to our cross
-
dehydrogenative silylation
at ambient temperature gave
2l
in 95% yield, providing a new syn-
thetic strategy for the construction of
advanced polysilane materi-
als.
19
To
the best of our k
nowledge, this is the
most diverse
scope of
hydrosilanes reported to date for any single catalytic C
–
H silylation
system.
T
he scope of the alkyne coupling partner
was likewise sub-
stantial, affording products containing
electron
-
rich and electron
-
deficient
aryl (
4a
–
j
), heteroaryl (
4k
–
m
), ferrocenyl (
4n
), and alkyl
(
4o
–
y
) groups (
Scheme 3
). Substrates containing sensitive func-
tional groups such as aryl halides (
4b
–
d
), an alkyl chloride (
4v
), and
a cyclopropane (
4r
) are tolerated without any undesired side rea
c-
tions. Molecules bearing acidic functionalities such as propargyla-
mines and
propargyl alcohols also react well, providing
4w
and
bis
-
silylated
4x
20
respectively in high yields. Unprecedented catalytic
cross
-
dehydrogen
ative silylation of
N
-
heterocyclic
systems, such as
those substrates containing an imidazole and a pyridine, are also
successful affording the
corresponding silylated building blocks
4k
Scheme
3
.
Scope of the alkyne partner
a
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent
for 24 or 48 h
at
the prescribed temperature.
Yields are of analytically pure isolated products
.
b
96 h for
4c
.
c
72 h for
4l
.
[Si] = PhMe
2
Si.
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Scheme 4.
Novel a
pplications
enabled by
alkali
hydroxide
–
catalyzed C(
sp
)
–
H silylation
a
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent at the prescribed temperature unless otherwise stated and y
ields are of analytically pure isolated
materials. See
SI for optimization and detailed experimental conditions.
b
For
7a
–
7c
M = K; for
7d
and
7e
: M = Na. See SI for specific conditions.
c
MAO = monoamine
oxidase.
d
<5% of Si
–
O product
was
detected.
and
4m
without any observed
Minisci
-
type reactivity. Substrates
containing C
–
H bonds that are susceptible to our KO
t
-
Bu
-
catalyzed
silylation,
4a
–
c
or those that could be engaged under a variety of other
C
–
H
functionalization chemistries
react
specifically at the terminal
alkyne C
–
H bo
nd. Thus, alkynylsilane products bearing toluene (
4f
),
anisole (
4g
), thiophene (
4l
and
4y
), propargyl ether (
4q)
, and phe-
nylethyl (
4t
) moieties could be readily accessed. In particular, elec-
tron
-
rich systems are excellent substrates and undergo the desired
C(
sp
)
–
H silylation to furnish alkynylsilanes containing aniline (
4e
),
dimethoxy benzene (
4h
), and ferrocene (
4n
) fragments without any
byproducts derived
from electrophilic silylation. T
he reaction scales
well as demonstrated by the
production of 19 grams
of
4s
using
1.5
molar equivalents of the hydrosilane
.
Synthetic utility of the products.
We next
proceeded to investigate novel appli
cations of our catalytic
method.
Symmetrical aliphatic or aromatic diynes
can either
un-
dergo
bis
-
functionalization
(
Scheme 4a
) to yield
5b
and
6b
or can
undergo catalytic mono
-
silylation to yield valuable desymmetrized
building blocks
5a
and
6a
by using an excess of substrate (see Sup-
plementary
Information). Hydroxide
-
catalyzed silylation followed
by
treatment
with a bo
rane (i.e., HBPin) leads to a one
-
pot catalytic
geminal
di
-
functionalization of terminal alkynes (
Scheme 4b
). This
protocol gives access to
tri
-
substituted olefins
7
a
–
e
containing both
a vinyl C
–
Si and C
–
B bond as a single olefin isomer from inexpen-
sive, c
ommercially available materials. Combinations of both alkyl
-
and aryl
-
substituted silanes and alkynes are amenable to this reac-
tion, though instability in some of the products
has been observed
during purification, resulting in decreased y
ields despite hig
h con-
versions.
21
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S
ila
-
drug analogues
in some cases demonstrate improved phar-
macokinetic properties relative to the cor
responding all
-
carbon
compounds and
are garnering increased attention from medicinal
chemists.
22
To evaluate our method for
late
-
stage
C
–
H silylation
ap-
plications, we subjected the monoamine oxidase (MAO) inhibitor
pargyline, the estrogen prodrug mestranol, and third
-
generation
oral contraceptive desogestrel to the catalytic silylation conditions,
successfully providing novel sila
-
drug a
nalogues
8
,
9
, and
1
0
respec-
tively (
Scheme 4c
).
Si
-
tethered diynes have a rich history in organometallic chemistry
and organic synthesis.
23
T
hey can be readily advanced to substituted
arenes, enones, dienes, and aromatic
N
-
heterocycles as well as
si-
loles, polysiloles or silole
-
heterocycle co
-
polymers.
8b
,
23,24
However,
synthesis
in general
remains
challenging and no stoichiometric or
catalytic methodology for the direct preparation of unsymmetrical
variants has been reported
. Using
the title
silylat
ion methodology,
symmetrical
a
lkyl
-
(
11a
and
11
b
)
and aryl
-
substituted
(
11
c
) variants
could be readily accessed
(
Scheme 4d
). This strategy also enabled an
unprecedented unsymmetrical coupling affording
variants
12
a
and
12
b
containing
aliphatic, aromatic,
and heteroaromatic
substituents
(see Supplementary Information).
Preliminary mechanistic considerations.
A number of mechanisms for the C(
sp
)
–
H silylation reaction occur-
ring under various conditions with different catalyst systems have
been proposed;
13
,
14a,15b
–
f,1
6
however, the
mechanistic details of this
al-
kali metal hydroxide
–
catalyzed
dehydro
silylation are not well un-
derstood at this point.
Nevertheless, a
number of experiments were
conducted to gain
insight
into
the underlying manifolds involved
.
As
a first investigation, we
conduct
ed
our reaction in the presence
of the radical traps TEMPO and galvinoxyl
(Scheme 5)
.
Scheme 5.
Influence of radical scavengers
a
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL
of solvent at the prescribed
temperature
and for the prescribed length of time
. Yields are
determined by GC analy-
sis using tridecane as an internal standard.
Scheme 6.
Impact of
of
alkali metal
ion chelators
a
a
Reaction
s were conducted on 0.5 mmol scale with 0.5 mL of solvent at the prescribed
temperature
and for the prescribed length of time
. Yields are
determined by GC analy-
sis using tridecane as an internal standard.
Neither additive completely thwarted the alkyne
C
–
H silylation:
TEMPO did not inhibit the reaction at 10% loading but lowered the
silylation yield at 300% loading; the addition of 10 mol% galvinoxyl
almost completely inhibited the reaction (Scheme 1). Although
these stable radical reagents could decrea
se the yield of the
ethynylsilane
2a
, these data certainly cannot conclude whether the
reaction is anionic in nature or whether it proceeds via single elec-
tron species. One can only conclude that galvinoxyl and TEMPO do
inhibit the reaction and that the fo
rmer is a more effective inhibitor.
We also studied the effect of potassium and sodium chelating
agents in the silylation reaction to investigate the importance of the
cation in the catalysis. When 18
-
crown
-
6 and 15
-
crown
-
5 were added
to reactions
usin
g KOH and NaOH as the catalysts
respectively,
quantitative silylation was still observed when using triethylsilane
as the
silicon partner, suggesting either that ineffective chelation of
the metal ion had occurred or that the cation was not necessary t
o
the reactivity in this particular case (
Scheme 6a
).
However,
in the case of triethoxysilane
, the addition of the che-
lating agent shut down reactivity, suggesting that the sodium ion is
Table 2
.
Comparison of
reactivity between
KO
t
-
Bu
and metal
hyd
roxide
catalysts
a
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent for 24 or 48 h at
the prescribed temperature. Yields are of analytically pure isolated products.
b
96 h for
4c
.
c
72 h for
4l.
[Si] =
PhMe
2
Si.
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indeed necessary for the silylation of alkynes with
this particular
silane
(Scheme
6
b).
In this case, the
only product when crown ethers
are added is (EtO)
4
Si, which indicates that sequestration of the al-
kali metal cation from the system shuts dow
n the productive C
–
H
silylation pathway and induces disproportionation of the silane.
While the counterion effect
i
s pronounced in
this case and also in a
number of others (see Table 2 and Table 3)
, the exact role
of
the
counterion remains an active area o
f research for this
methodology
.
Table 3
.
Comparison of reactivity between NaOH and KOH cat-
alysts.
a
a
Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent for 24 or 48 h at
the prescribed temperature. Yields are of analytically pure isolated products.
b
96 h for
4c
.
c
72 h for
4l.
[Si] = PhMe
2
Si.
Nevertheless
, it
is becoming
increasingly a
pparent
that the iden-
tity of the
base
catalyst
in this dehydrocoupling
is
unusually
im-
portant
and extends far beyond a simple consideration of basicity
.
For a number of substrates, we have directly compared several cat-
alysts: KO
t
-
Bu, which is an adept sily
lation catalyst in our recently
reported cross
-
dehydrogenative C
–
H silylation of aromatic
hetero-
cycles
and showed good reactivity for the title reaction (Table 1)
,
4a
–
c
and KOH and NaOH, which
are exceptional catalysts for the
silyla-
tion of C(
sp
)
–
H bonds in this report.
To perform this comparison
, several alkyne substrates and silanes
were subjected to the reaction using KO
t
-
Bu as a catalyst
, with the
corresponding NaOH
-
catalyzed reaction performed in parallel
. In
the reaction of cyclohexylp
ropyne
1
with triethylsilane, KO
t
-
Bu suc-
cessfully produced the silylated alkyne in moderate yield (
recall
Ta-
ble 1
, entry 1
). H
owever, in virtually all other investigated cases, KO
t
-
Bu failed to convert the starting material or produced only trace
quantitie
s of the desired dehydrocoupling
product
(Table 2)
. These
data were
striking and unanticipated
and
suggest
that the acetylinic
silylation described in this report and the heterocyclic
silylation de-
scribed previously
require different catalysts and very we
ll may pro-
ceed via distinct mechanisms.
These results also suggest that cata-
lysts that do not lie within an optimal pKa range
–
whether too basic
or not basic enough
–
perform poorly; this in turn may explain why
the superbase
-
catalyzed (i.e.,
MgO, KNH
2
/Al
2
O
3
, LiAlH4,
n
-
BuLi,
metal alkoxide) protocols discussed in the introduction
13c
–
f
have suf-
fered from such poor substrate scope.
Next,
we were interested in directly comparing the reactivity of
NaOH and KOH in the dehydrosilylation since during our
evalua-
tion of t
he hydrosilane scope (Scheme 2)
we had observed that de-
pending on the nature of the hydrosilane employed, either NaOH or
KOH was preferred
.
In order to conduct a more detailed study of
this phenomenon, we subjected a variety of hydrosilanes
and alkyne
substrates to the standard reaction conditions employing NaOH
and KOH as the catalysts in parallel. These data, which are pre-
sented in Table 3, clearly demonstrate the
ma
rked difference in the
reactivity of the substrates presented depending on
the choice of al-
kali hydroxide employed. H
owever, in our opinion
,
there appears to
be no immediately discernable trend (i.e., basicity, aggregation
states, solubilities) that explains the
difference
in the performance
of the two catalysts. The differences
between NaOH and KOH are
most pronounced when using different silanes (
Table 3,
entries 1
-
6);
however, most substrates studied performed better using NaOH, ra-
ther than KOH, except for the notable cases of
the steroidal deriva-
tives (entries 14 and 15)
, whic
h displayed no silylation when using
NaOH.
To date, the nature of this
remarkable
effect is unclear and
experimentation remains the best method to determine the optimal
catalyst
-
substrate combination.
In conclusion, we have disclosed an alkali metal hy
droxide
–
cata-
lyzed cross
-
dehydrogenative C(
sp
)
–
H silylation method. The chem-
istry proceeds under mild conditions and enables the direct synthe-
sis of a wide array of useful alkynylsilanes
–
with high tunability in
both the alkyne and hydrosilane
–
many of wh
ich are challenging to
prepare by alternate means. The
p
reliminary
mechanistic
studies
and empirical results
point to a
mechanism
that
is
likely
distinct
from previously disclosed cross
-
dehydrogenative C
–
H silylation re-
actions in general, including the rec
ently reported KO
t
-
Bu
-
cata-
lyzed C(
sp
2
)
–
H silylation of heteroarenes.
4a
–
c
Although the mecha-
nism currently remains elusive
, i
t is likely that the
presumed
avoid-
ance of conventional superbase, electrophilic silylation, and C
–
H in-
sertion mechanisms, which ha
ve been the focus of prior strategies
,
must
be at least partly responsible for
the
title
method’s unprece-
dented scope
and reactivity profile
.
Additionally intriguing is the
dramatic effect of the nature of the basic catalyst on reaction out-
come as
evidenced by the difference in dehydrosilylation reactivity
between alkali metal hydroxides and KO
t
-
Bu and between NaOH
and KOH.
Detailed
mechanistic studies by computational and ex-
perimental
methods are underway.
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ASSOCIATED CONTENT
Supporting Information
Available:
Experimental details, analytics, and supporting experiments.
AUTHOR INFORMATION
§
AF current address: Department of Chemistry and Applied Biosciences,
ETH Zürich, Vladimir
-
Prelog
-
Weg 2, CH
-
8093, Zürich, Switzerland
.
Corresponding Author
rhg@caltech.edu
,
stoltz@caltech.edu
Author Contributions
†
The
se
authors
contributed equally
.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work
was supported by the NSF under the CCI Center for
Se-
lective C
–
H Functionalization (CHE
-
1205646) and under CHE
-
1212767. A.A.T. is grateful to Bristol
–
Myers Squibb,
the Resnick Sus-
tainability Institute at Caltech
, and to
Dow Chemical
for predoctoral
fellowsh
ips
as well as
t
o NSERC for a PGS D fellowship.
D.P.S
thanks
the CCI Center for Selective C
–
H Functionalization
for support
.
W.
-
B.L thanks The Shanghai Institute of Organic Chemistry (SIOC) and
S.
-
L. You for a postdoctoral fellowship.
We thank S. Virgil
and the
Caltech Center for Catalysis and Chemical Synthesis for
access to
analytical equipment
. M. Shahgoli and N. Torian
(Caltech)
are
acknowledged for assistance with high
-
resolution mass spectrome-
try
.
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