Alkali metal-hydroxide-catalyzed C(sp)-H Bond silylation

Article abstract of DOI:10.1021/jacs.6b12114

Disclosed is a mild, scalable, and chemoselective catalytic 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 entry point into various organosilane building blocks and additionally enabling the discovery of a number of novel synthetic strategies. Remarkably, the optimal catalysts are NaOH and KOH.

Full text of DOI:10.1021/jacs.6b12114

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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–catalyzed 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. Stoltz1*
& Robert H. Grubbs1*
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1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, 91125, USA
Supporting Information Placeholder
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
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 catalysts are NaOH and KOH.
Scheme 1. Approaches to C–H silylation of alkynes
Introduction.
The catalytic transformation of C–H bonds into a variety of useful
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, sustainable, 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(sp2)–H silylation of aromatic heterocy-
cles with hydrosilanes using catalytic potassium tert-butoxide (KOt-
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 used in the construction of electronically
and structurally interesting materials,5 employed as substrates in
metathesis reactions6 and cycloadditions,7 and as precursors to het-
erocycles8 and polycyclic aromatic frameworks.9 Moreover, al-
kynylsilane nucleophiles and cross-coupling partners react under
mild conditions10 and therefore are commonly utilized 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., [18F]PET) probes with high in vivo stability for
non-invasive biomedical imaging applications.12
those reactions. An NHC/NaH-catalyzed protocol that is tolerant of
N-heterocycles has been reported; however, the use of CF3SiMe3
(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
Strategies for the synthesis of alkynylsilanes have employed
strong bases (Scheme 1a, Route A)13 or have relied on stoichio-
metric14 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–NR2],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 acceptors15f 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 design. Interestingly, highly basic species such as
MgO,13c,e,f KNH2/Al2O3,13g LiAlH4,13c,e n-BuLi,13c and even alkoxides13c
have shown some catalytic activity in the dehydrocoupling of hy-
drosilanes and alkynes. However, these reports are limited to only a
handful of unfunctionalized examples, the reactions give modest
yields and selectivities, and the chemistry typically requires elevated
Table 1. Reaction discovery and catalyst evaluationa
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 materials. Reaction does not proceed without catalyst.
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bond silylation of unprecedented scope. The method avoids the fun-
providing a point of entry into novel alkynylsilyl [18F]PET radiophar-
damental limitations of previous strategies, including classical stoi-
chiometric deprotonation and catalytic transition metal–catalyzed
approaches, and uses readily available KOH or NaOH as the optimal
catalysts (Scheme 1b).
maceutical moieties.12 Using Me3Si–SiHMe2 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 knowledge, this is the most diverse scope of
hydrosilanes reported to date for any single catalytic C–H silylation
system. The 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 reac-
tions. Molecules bearing acidic functionalities such as propargyla-
mines and propargyl alcohols also react well, providing 4w and bis-
silylated 4x20 respectively in high yields. Unprecedented catalytic
cross-dehydrogenative 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
Results and Discussion.
We initiated investigations with the silylation of alkyne 1 using
Et3SiH under our previously reported KOt-Bu-catalyzed C(sp2)–H si-
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–
lylation conditions4a c and gratifyingly observed alkynylsilane 2a in
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good yield; however, along with 9% of undesired alkyne migration
product 1-iso (Scheme 2, entry 1).17 NaOt-Bu (entry 2) and LiOt-Bu
(entry 3) show poor reactivity, and pyridine (entry 4) gives no reac-
tion. KOH is superior to KOt-Bu (entry 5), generating the desired
product in 95% yield with decreased quantities (3%) of the unde-
sired 1-iso. Moving from Et3SiH to PhMe2SiH permits the reaction
to occur at ambient temperature while still maintaining high yield
(entry 6). In sharp contrast to our previously reported heteroarene
C(sp2)–H silylation protocol wherein the catalyst was essentially
limited to KOt-Bu,4a–c the ideal catalysts for the C(sp)–H silylation
were KOH and NaOH affording 2b in 89% and 93% 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 alkyl- 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 enabled 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, alkynyl dime-
thylsilylpyridines 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 seemingly 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 3. Scope of the alkyne partnera
Scheme 2. Scope of the hydrosilanea,b
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] = PhMe2Si.
a Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent at the prescribed
temperature. bReactions are run for 48 h, except 24 h for 2c and 2e.
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Scheme 4. Novel applications enabled by alkali hydroxide–catalyzed C(sp)–H silylationa
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a Reactions were conducted on 0.5 mmol scale with 0.5 mL of solvent at the prescribed temperature unless otherwise stated and yields 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
Synthetic utility of the products.
containing C–H bonds that are susceptible to our KOt-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 bond. 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. The reaction scales
well as demonstrated by the production of 19 grams of 4s using 1.5
molar equivalents of the hydrosilane.
We next proceeded to investigate novel applications 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 borane (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 7a–e containing both
a vinyl C–Si and C–B bond as a single olefin isomer from inexpen-
sive, commercially 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 yields despite high con-
versions.21
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Sila-drug analogues in some cases demonstrate improved phar-
Neither additive completely thwarted the alkyne C–H silylation:
macokinetic properties relative to the corresponding 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 analogues 8, 9, and 10 respec-
tively (Scheme 4c).
Si-tethered diynes have a rich history in organometallic chemistry
and organic synthesis.23 They 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 silylation methodology,
symmetrical alkyl- (11a and 11b) and aryl-substituted (11c) variants
could be readily accessed (Scheme 4d). This strategy also enabled an
unprecedented unsymmetrical coupling affording variants 12a and
12b containing aliphatic, aromatic, and heteroaromatic substituents
(see Supplementary Information).
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 decrease 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 former 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 using 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 to
the reactivity in this particular case (Scheme 6a).
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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 KOt-Bu and metal
hydroxide catalysts a
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,16 however, the mechanistic details of this al-
kali metal hydroxide–catalyzed dehydrosilylation 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 conducted our reaction in the presence
of the radical traps TEMPO and galvinoxyl (Scheme 5).
Scheme 5. Influence of radical scavengersa
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 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] = PhMe2Si.
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.
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indeed necessary for the silylation of alkynes with this particular
reported cross-dehydrogenative C–H silylation of aromatic hetero-
silane (Scheme 6b). In this case, the only product when crown ethers
are added is (EtO)4Si, which indicates that sequestration of the al-
kali metal cation from the system shuts down the productive C–H
silylation pathway and induces disproportionation of the silane.
While the counterion effect is 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 of research for this methodology.
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 KOt-Bu as a catalyst, with the
corresponding NaOH-catalyzed reaction performed in parallel. In
the reaction of cyclohexylpropyne 1 with triethylsilane, KOt-Bu suc-
cessfully produced the silylated alkyne in moderate yield (recall Ta-
ble 1, entry 1). However, in virtually all other investigated cases, KOt-
Bu failed to convert the starting material or produced only trace
quantities 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 well 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, KNH2/Al2O3, LiAlH4, n-BuLi,
metal alkoxide) protocols discussed in the introduction13c–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 the 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 marked difference in the
reactivity of the substrates presented depending on the choice of al-
kali hydroxide employed. However, 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), which 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 hydroxide–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 which are challenging to
prepare by alternate means. The preliminary 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 recently reported KOt-Bu-cata-
lyzed C(sp2)–H silylation of heteroarenes.4a–c Although the mecha-
nism currently remains elusive, it is likely that the presumed avoid-
ance of conventional superbase, electrophilic silylation, and C–H in-
sertion mechanisms, which have 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 KOt-Bu and between NaOH
and KOH. Detailed mechanistic studies by computational and ex-
perimental methods are underway.
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Table 3. Comparison of reactivity between NaOH and KOH cat-
alysts. a
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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] = PhMe2Si.
Nevertheless, it is becoming increasingly apparent 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: KOt-Bu, which is an adept silylation catalyst in our recently
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AUTHOR INFORMATION
§AF current address: Department of Chemistry and Applied Biosciences,
ETH Zürich, Vladimir-Prelog-Weg 2, CH-8093, Zürich, Switzerland.
Corresponding Author
9
rhg@caltech.edu, stoltz@caltech.edu
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interests.
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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
fellowships as well as to 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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