Iridium-Catalyzed Silylation of C-H Bonds in Unactivated Arenes: A Sterically Encumbered Phenanthroline Ligand Accelerates Catalysis

Article abstract of DOI:10.1021/jacs.9b01972

We report a new system for the silylation of aryl C-H bonds. The combination of [Ir(cod)(OMe)]₂ and 2,9-Me₂-phenanthroline (2,9-Me₂-phen) catalyzes the silylation of arenes at lower temperatures and with faster rates than

Full text of DOI:10.1021/jacs.9b01972

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Article
Iridium-Catalyzed Silylation of C-H bonds in Unactivated
Arenes: A Sterically-Encumbered Phenanthroline
Ligand Accelerates Catalysis Enabling New Reactivity
Caleb Karmel, Zhewei Chen, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01972 • Publication Date (Web): 11 Apr 2019
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Iridium-Catalyzed Silylation of C-H bonds in Unactivated Arenes: A
Sterically-Encumbered Phenanthroline Ligand Accelerates Catalysis
Caleb Karmel‡, Zhewei Chen‡, and John F. Hartwig*
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Department of Chemistry, University of California, Berkeley, California, 94720, United States
Supporting Information Placeholder
ABSTRACT: We report a new system for the silylation of aryl C-H bonds. The combination of [Ir(cod)(OMe)]2 and 2,9-Me2-
phenanthroline (2,9-Me2phen) catalyzes the silylation of arenes at lower temperatures and with faster rates than those re-
ported previously, when the hydrogen byproduct is removed, and with high functional group tolerance and regioselectivity.
Inhibition of reactions by the H2 byproduct is shown to limit the silylation of aryl C-H bonds in the presence of the most active
catalysts, thereby masking their high activity. Analysis of initial rates uncovered the high reactivity of the catalyst containing
the sterically hindered 2,9-Me2phen ligand but accompanying rapid inhibition by hydrogen. With this catalyst, under a flow
of nitrogen to remove hydrogen, electron-rich arenes, including those containing sensitive functional groups, undergo silyla-
tion in high yield for the first time, and arenes that underwent silylation with prior catalysts react over much shorter times
with lower catalyst loadings. The synthetic value of this methodology is demonstrated by the preparation of key intermediates
in the synthesis of medicinally important compounds in concise sequences comprising silylation and functionalization. Mech-
anistic studies demonstrate that the cleavage of the aryl C-H bond is reversible and that the higher rates observed with the
2,9-Me2phen ligand is due to a more thermodynamically favorable oxidative addition of aryl C-H bonds.
of C-H bonds. However, these reactions require large excess
INTRODUCTION
of the arene9 or a directing group.10
The functionalization of C-H bonds in arenes and alkanes
is becoming a valuable methodology for the synthesis of
pharmaceutical drug candidates,1 and the reactions of bo-
ranes and diboranes with arenes catalyzed by transition-
metal complexes have proven particularly useful. These re-
actions occur at the most electron-poor C-H bond that is ste-
rically accessible, and this regioselectivity is complemen-
tary to electrophilic aromatic substitutions, which generally
occur at the most electron-rich position.2 The products of
these reactions are versatile synthetic intermediates that
undergo further halogenation, cyanation, etherification, hy-
droxylation, amination, and trifluoromethylation,3 as well
as cross-coupling reactions to form carbon-carbon bonds
that are widely employed in medicinal chemistry.4
Scheme 1. Functionalization of Aryl C-H bonds With Bo-
ron and Silicon Reagents
Although the functionalizations of aryl C-H bonds with
boron reagents are useful, several features of these reac-
tions could limit broad utility. For example, the reagents can
be expensive relative to the value of the products, some het-
eroarylboronates are unstable to protodeboronation, and
the lengthy synthesis of diboron reagents can lead to large
amounts of waste.5 The functionalization of C-H bonds with
silanes is an attractive alternative to the functionalization
with boranes because many silanes are produced and con-
sumed on a large scale,6 silylarenes containing heteroatom
substituents attached to silicon can be employed in a wide
range of coupling reactions and oxidative transformations,7
and the heteroarylsilanes are more stable than heteroaryl-
boronates.7d, 8 Several groups have reported silylations of
the C-H bonds of arenes with trialkylsilanes, difluoroal-
kylsilanes, silatrane, or siloxysilanes catalyzed by com-
plexes that are similar to those that catalyze the borylation
Our group has reported silylations of aryl C-H bonds with
the arene as limiting reagent catalyzed by rhodium and irid-
ium complexes with the silane HSiMe(OTMS)2, which is
available in bulk at low cost.11 Due to the presence of two
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heteroatoms attached to the central silicon, the silylarenes complexes of phenanthrolines bearing methyl groups in the
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produced from the functionalization of aryl and heteroaryl
C-H bonds with this reagent undergo a wide variety of
cross-coupling and functionalization reactions.8 The silyla-
tions catalyzed by a rhodium-bisphosphine complex we re-
ported functionalize arenes with high sterically-derived re-
gioselectivity. However, a series of functional groups, in-
cluding Lewis basic groups, such as nitriles, most basic het-
erocycles, and reducible groups, such as aryl iodides, aryl
bromides, aryl esters, and ketones, did not undergo silyla-
tion (Scheme 1b).12 In contrast, the silylations catalyzed by
an iridium complex of 2,4,7-trimethyl phenanthroline oc-
curred with exceptionally high functional-group tolerance.
Yet, reactions catalyzed by this system required long times
and required high temperatures to reach high conversion of
starting material. Furthermore, the reactions of electron-
neutral arenes occurred in only modest yields, and the reac-
tions of electron rich arenes formed little to no product
(Scheme 1c).13
2 and the 9 positions were more than five times faster than
those catalyzed by iridium complexes of the 2, 4, 7-substi-
tuted phenanthroline L2 previously reported for the silyla-
tion of C-H bonds.
Despite the high initial rate of the silylation catalyzed by
the combination of [Ir(COD)(OMe]2 and 2,9-Me2phen, the
overall yield of this reaction was reported to be lower than
that of the reaction catalyzed by complexes containing other
ligands.13 Indeed, when the reaction of benzene and silane
catalyzed by iridium and this ligand approached 5% conver-
sion, the rate began to decrease (Figure 1), and after 15%
conversion, the amount of silylbenzene produced by the re-
action conducted with 2-methyl ligand L2 is greater than
that produced by the catalyst containing 2,9-dimethyl lig-
ands L1 or L4. We hypothesized that inhibition of the cata-
lyst by the hydrogen produced by the reaction could cause
the observed decrease in rates during reactions catalyzed
by complexes ligated by L1 or L4.
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Here, we describe a new iridium catalyst and conditions
for the silylation of arenes with hydrosilanes that together
lead to reactions of electron-rich arenes and much faster re-
actions of heteroarenes and electron-poor arenes, along
with experimental mechanistic studies that reveal the
origin of this high reactivity. This catalyst contains 2,9-di-
methylphenanthroline (2,9-Me2phen) as ligand. The high
activity of this catalyst is masked under standard conditions
by its susceptibility to inhibition by the hydrogen byprod-
uct. The high activity is evident from initial rates and be-
comes practical when the product inhibition is alleviated by
removing the hydrogen from the system. Cleavage of the
aryl C-H bond is reversible, and the higher rates, counterin-
tuitively, appear to result from a more thermodynamically
favorable oxidative addition of C-H bonds to the iridium
complex of this hindered ligand than to complexes of lig-
ands lacking substituents in the 2 and 9 positions. Applica-
tions to the synthesis of a series of intermediates to medici-
nally important compounds demonstrate the value of this
new system.
To determine whether hydrogen inhibited the silylation
reaction, we first measured the amount of silylbenzene
formed in the presence of [Ir(COD)(OMe]2 and L1 with
added dihydrogen. The rate at which silylbenzene is formed
is ten times slower under an atmosphere of hydrogen than
under an atmosphere of nitrogen (See SI). We examined
whether a series of hydrogen acceptors could prevent inhi-
bition by hydrogen formed in the course of the reaction. The
profile of the reaction of benzene and silane was the same
in the presence or absence of cyclohexene or tetrameth-
ylethylene as hydrogen acceptors (Figure 2). Consistent
with this observation, the 1H NMR spectrum of the crude re-
action catalyzed by iridium and 2,9-Me2phen with cyclohex-
ene as the hydrogen acceptor contained signals correspond-
ing to less than 0.05 equivalents of cyclohexane, even
though 16% of the starting material was converted to prod-
uct. This result shows that the rate of the reduction of cyclo-
hexene is much lower than the rate of the silylation of ben-
zene. The conversion of silane in the reaction conducted
with the strained alkene norbornene (nbe) was higher in
less time than that in reactions conducted with other hydro-
gen acceptors, but the silylation of the alkene C-H bond of
nbe to form vinylsilane was faster than silylation of the C-H
bond of benzene, and a low yield of silylarene was observed.
Thus, the complex formed by the combination of iridium
and 2,9-Me2phen and silane does not reduce unstrained in-
ternal alkenes with hydrogen at a rate that is commensurate
with the rate of the silylation of benzene, and this complex
leads to the silylation of the C-H bond of a strained alkene.
For this reason, a different approach to removing hydrogen
from the reaction was required to prevent the inhibition of
the catalysts by hydrogen.
Results and Discussion
1. Initial Rates and Reaction Development
To identify highly active catalysts for the silylation of aryl
C-H bonds, including those of electron-rich arenes, we first
measured the rates of the silylation of benzene in the pres-
ence of an iridium pre-catalyst and phenanthrolines pos-
sessing varied steric properties. The initial rate of the reac-
tion of HSiMe(OTMS)2 and benzene was determined by
measuring the amount of silyl-arene produced at 80 °C with
a 1:1.5 ratio of benzene to silane (Figure 1). The rates of re-
actions catalyzed by the combination of
1 mol %
To test further the effect of the hydrogen byproduct, the
reaction was run in a closed system, as is typically done for
reactions on small scale, as well as a system containing a
flow of nitrogen. The reaction of o-xylene and silane cata-
lyzed by [Ir(cod)(OMe)]2 and 2,9-Me2Phen in a closed vial
produced only the silylarene in only 18% yield. However,
the same reaction conducted in a vessel equipped with a ni-
trogen inlet and gas outlet formed silylarene 4 in 77% yield
within 20 h. It appears that the flow of nitrogen gas through
the system prevents catalyst inhibition by removing
[Ir(COD)(OMe]2 and 3 mol % of four phenanthroline ligands
(L1-L4, Figure 1) containing methyl substituents in differ-
ent quantities and positions were measured. The initial
rates of the reactions catalyzed by the combination of irid-
ium and a phenanthroline containing methyl groups in the
2 and the 9 positions (L1 and L4) are higher than those of
the reactions catalyzed by the combination of iridium and
phenanthroline ligands lacking one or both of the methyl
groups in the 2 and the 9 positions (L2 and L3) (Figure 1).
The silylation of aryl C-H bonds catalyzed by iridium-
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Figure 1. Measurement of Rate of Silylation and Reaction Profile with Different Iridium Catalystsa
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0.2
0.15
0.1
0.035
0.03
0.025
0.02
0.015
0.01
0.005
0
L1
L2
krel = 5.5
krel = 1
r2 = 0.99
L1
L2
L3
L4
r2 = 1.0
0.05
0
0
10000
t (s)
20000
0
50000 100000
t (s)
aConditions: benzene (0.25 mmol), HSiMe(OTMS)2 (1.5 equiv), tetramethylethylene (1.0 equiv), [Ir(cod)(OMe)]2 (1.0 mol %), ligand
(3.0 mol %), dodecane (1.0 equiv), THF (1 M). Silylarene concentration was determined by GC using n-dodecane as an internal stand-
ard.
Figure 2. Measurement of Rate of Silylation and Reac-
tion Profile with a Series of Hydrogen Acceptorsa
hydrogen gas and allows reactions catalyzed by iridium
complexes ligated by 2,9-Me2Phen to reach high conversion.
2. Scope of the Silylation of Aryl C-H Bonds
Having identified a combination of ligand that generates
a highly active catalyst and having gained evidence that the
catalyst activity is inhibited by the hydrogen byproduct, we
explored the scope of the reactions catalyzed by the com-
plex of 2,9-dimethyl ligand L1 under conditions in which
hydrogen is removed by a flow of nitrogen. Most reactions
were conducted in a Radley Carousel Reactor equipped with
nitrogen inlet and outlets, heating block and cooling jacket.
Under these conditions, electron-rich, electron-neutral,
electron-poor and heteroaromatic silylarene products were
obtained in high yields from reactions catalyzed by iridium
complexes of L1. Silylarenes also were produced in high
yield from reactions conducted in a simple round-bottom
flask fitted with a reflux condenser and a nitrogen inlet and
gas outlet.
0.1
0.08
A1
0.06
0.04
A2
A3
A4
0.02
The dramatic increase in rates of reactions catalyzed by
the complex of 2,9-Me2phen enabled the first iridium-cata-
lyzed silylations of electron-rich arenes with the arene as
limiting reagent. Arenes containing alkyl, methoxy and di-
methylamino substituents were obtained in yields ranging
from 66% to 94% (Table 1). The silylation of 1,3-dimethox-
ybenzene occurred with >10:1 selectivity for functionaliza-
tion at the meta C-H bond over the ortho C-H bond. In all
other cases, the sole C-H bond that reacted was distal to
functional groups on the arene. To assess whether the influ-
ence of the steric properties of the C-H bonds on the selec-
tivity of the silylation reaction was larger than the effect of
0
0
1000 2000 3000 4000
t (s)
aConditions: benzene (0.25 mmol), HSiMe(OTMS)2 (1.5
equiv), hydrogen acceptor (1.0 equiv), [Ir(cod)(OMe)]2 (1.0
mol %), 2,9-Me2Phen (2.0 mol %), dodecane (1.0 equiv), THF
(1 M). Silylarene concentration was determined by GC using n-
dodecane as an internal standard.
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the electronic properties of the arene and whether reac- demonstrate that previously reported systems for the irid-
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tions would occur at particularly electron-rich C-H bonds,
the reaction of 2,6-dimethylanisole was conducted. The C-H
bond that is para to the electron-donating methoxy group in
this arene is particularly electron rich, due to the presence
of three substituents that are electron-donating to the C-H
bond at the sterically accessible 5-position. Despite the high
electron density at this C-H bond, the reaction occurred ex-
clusively to form the 5-silylarene 8 in a high 83% yield.
ium-catalyzed silylation of aryl C-H bonds would require
unacceptably high catalyst loadings to produce reasonable
yields of electron-rich silylarenes.
Electron-neutral and electron-poor arenes underwent C-
H silylation in yields that ranged from 56% to 99% (Table
2). The reactions of these substrates occurred with high
functional
Table 2. C-H Silylation of Electron-Neutral Arenes (top)
and Electron-Poor Arenes (bottom)a
Table 1. C-H Silylation of Electron-Rich Arenesa
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aConditions for reactions with L1: Arene (0.5 mmol),
HSiMe(OTMS)2 (1.5 equiv), [Ir(cod)(OMe)]2 (1 mol %), ligand
(2 mol %), 1,4-dioxane (200 µL), 100 °C, under a stream of N2,
20-24 h. Isolated yields reported. Conditions for reactions with
L2 and L3: Arene (0.5 mmol), HSiMe(OTMS)2 (1.5 equiv),
[Ir(cod)(OMe)]2 (1 mol %), ligand (2 mol %), 1,4-dioxane (200
µL), 100 °C, under a stream of N2, 20 h. Yield was determined
by NMR spectroscopy relative to CH2Br2 internal standard.
aConditions for reactions with L1: Arene (0.5 mmol),
HSiMe(OTMS)2 (1.5 equiv), [Ir(cod)(OMe)]2 (1 mol %), ligand
(2 mol %), 1,4-dioxane (200 µL), 100 °C, under a stream of N2,
6-24 h. Isolated yields reported. Conditions for reactions with
L2 and L3: Arene (0.1 mmol), HSiMe(OTMS)2 (1.5 equiv), cy-
clohexene (1.5 equiv), [Ir(cod)(OMe)]2 (1 mol %), ligand (2 mol
%), THF (100 µL), 100 °C. Yield was determined by NMR spec-
troscopy relative to CH2Br2 internal standard. bConducted at 80
°C. cYield was determined by NMR spectroscopy relative to
CH2Br2 internal standard. 0.2-0.25% [Ir(cod)(OMe)]2, 18 h.
d4% [Ir(cod)(OMe)]2, 20 h.
c
bConducted at 80 °C. Yield was determined by NMR spectros-
copy relative to CH2Br2 internal standard.
To assess the effect of the ligand on the reactions of elec-
tron-rich arenes, we also conducted the silylations with the
catalyst generated from 2,4,7-Me3phen and 3,4,7,8-tetrame-
thyl phenanthroline. The reactions of electron-rich arenes
conducted with 2,4,7-Me3phen instead of 2,9-Me2phen
formed silylarenes in low yields, whether the reaction was
conducted under a flow of nitrogen or in a closed system
with alkene hydrogen acceptor. The yields from reactions of
these arenes under a flow of nitrogen catalyzed by iridium
and 2,4,7-Me3phen (L2) ranged from 5% (5) to 34% (6). No
electron-rich silylarene products were obtained from reac-
tions catalyzed by iridium and Me4phen (L3). These results
group tolerance in less than 20 h. Esters were tolerated; no
products from reduction of this functionality were observed
(13, 16 and 20). Likewise, two representative benzonitriles
underwent silylation in 84% (15) and 97% (18) yield
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without any detectable reduction of the cyano groups. substrates. As was observed for reactions of aryl halides, re-
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These reactions occurred with >10:1 selectivity for func-
tionalization at the meta C-H bond over the ortho C-H bond.
Borylation of benzonitriles often occurs to give mixtures of
products from reaction ortho and meta to the cyano
group.14 Silylarenes containing iodo, bromo or chloro sub-
stituents were obtained in high yield without hydrodehalo-
genation (substrates: 12, 14, 18, 20-23).
actions of heteroaryl halides occurred without proto-
dehalogenation. The reactions of heteroarenes also oc-
curred with the same tolerance for carbonyl groups ob-
served in the reactions of arenes. Furyl ketone 25 under-
went silylation in 97% yield without any reduction of the
carbonyl group. The silylation of thiophenes and furans oc-
curred exclusively at the 2-position. Indole 24 underwent
silylation with high selectivity for the 2-position over the 3-
position (2-Si:3-Si = 17:1). 2,6-Dichloropyridine underwent
silylation exclusively at the 4-position in 77% yield.
The reactions catalyzed by complexes of the previously
reported ligands (L2 or L3 with added hydrogen acceptor)
form electron-neutral silylarene products in much lower
yields under similar conditions. Most of these electron-neu-
tral silylarenes (Table 2, top) were produced in acceptable
yield in reactions catalyzed by iridium ligated by L2, but
these reactions required days to reach high conversion. The
conversion of electron-neutral arenes to the corresponding
silylarenes catalyzed by the complex of L2, after 20 hours,
ranged from low (16, 31%) to modest (14, 58%). In con-
trast, the conversion of electron-neutral arenes into the cor-
responding silylarenes was complete after 20 hours when
catalyzed by the complex of L1.
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Table 3. C-H Silylation of Heteroarenesa
Arenes in which all C-H bonds are ortho to a substituent
were silylated, but the rates of these reactions were low. For
example, the reaction of 3,4-dimethoxytoluene formed the
silylarene resulting from C-H activation ortho to the meth-
oxy group. However, only 4% yield of 11 was observed after
2 d, even with a higher catalyst loading of 4%.
In some cases, running the silylation reaction in a closed
system with a hydrogen acceptor is more convenient than
running the reaction under a flow of nitrogen. We hypothe-
sized that the rates of the silylation of heteroarenes might
be significantly faster than the rate of the competitive silyla-
tion of a norbornenyl C-H bond, allowing this alkene to be
employed as hydrogen acceptor in a closed system. As
shown in Table 3, both 5-membered and 6-membered ring
heterocycles underwent silylation with norbornene as ac-
ceptor or in an open system in high yields under conditions
that are milder than those for the silylation of aromatic
Scheme 2. Reported Functionalizations of Silylarene Products
aConditions with norbornene: Arene (0.25 mmol),
HSiMe(OTMS)2 (1.5 equiv), norbornene (1 equiv),
[Ir(cod)(OMe)]2 (1 mol %), ligand (2 mol %), THF (100 µL), 100
°C, 2 h. Isolated yields reported. Conditions with open system:
Arene (0.5 mmol), HSiMe(OTMS)2 (1.5 equiv), [Ir(cod)(OMe)]2
(1 mol %), ligand (2 mol %), 1,4-dioxane (200 µL), 50-60 °C,
under a stream of N2, 20 h. Isolated yields reported. *Yield was
determined by NMR spectroscopy relative to CH2Br2 internal
standard.
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Scheme 3. Disconnections of Doravirine (top), Ozenoxa-
cin (middle) and AR-C123196 (bottom)
3. Functionalizations of Silylarenes
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9
The transformations of the silyl group of these silylarenes
into common functional groups is well documented and un-
derscore the value of these silylation reactions (Scheme 2).
Silylarene 21 has undergone cross-coupling reactions me-
diated by copper with a broad range of nitrogen nucleo-
philes including anilines, pyrroles, amides, sulfonamides
and alkyl amines with yields of aniline products that range
from 41% to 78%. The coupling of 4, 15, and 20 with am-
ides has also been reported.15 Tamao-Fleming oxidation of
silylarene 9 has been reported to form 3,5-dimethoxyphe-
nol in 69% yield.12 Silylarene 15 also has been iodinated us-
ing ICl.13 Silylarene 19 has been coupled with 3-iodoanisole
in a reaction catalyzed by palladium to produce biaryl prod-
uct in 58% yield.12 Finally, 4, 15, 20, and 21 have been con-
verted into the corresponding trifluoromethyl arenes in
34% to 75% yield by reaction with (phenanthroline)CuCF3
in the presence of fluoride activator.16 Clearly, the si-
lylarenes formed by the reactions reported here are versa-
tile intermediates that can be transformed into aryl halides
and phenols in good yields and coupled with haloarenes,
amines, anilines and sources of trifluoromethyl groups in
modest to good yields.12-13, 15-16
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Three routes to related intermediates in the synthesis of
doravirine are shown in Scheme 4. The first route, reported
by Merck, starts from m-chloroiodobenzene and comprises
the borylation of the C-H bond of the arene in the 5-position
and oxidation to generate 1,3,5-chloroiodophenol. Aryl io-
dides are produced on a smaller scale than phenols, and the
iodide in in this molecule is ultimately transformed into a
nitrile. Thus, it might be preferable to start the synthesis
from an arene that contains the nitrile or to install the iodide
by C-H activation. However, the borylation of 3-chloroben-
zonitrile generates a mixture of products, which result from
monoborylation ortho and meta to the nitrile and from di-
borylation. An alternative synthesis by the borylation of a
protected phenol, such as 34, would form a single aryl-
boronate, but iodination of arylboronic esters generally oc-
curs in only modest yield.20 In contrast, entry 7 of Table 2
above, shows that the silylation of 3-chlorobenzonitrile oc-
curred with excellent selectivity for the meta position with-
out formation of any product from disilylation. We found
that silylarene 18 undergoes oxidation with hydrogen per-
oxide to generate phenol 30 in 55% yield from the arene
over two steps. Alternatively, acyl-protected 3-chlorophe-
nol, 34, underwent silylation in high yield. Iodination with
ICl afforded iodoarene 35, an acyl protected form on the in-
termediates in 89% isolated yield over two steps.
4. Synthesis of Pharmaceutical Intermediates
To demonstrate the applicability of the silylation of C-H
bonds, we synthesized arenes and heteroarenes that are in-
termediates in synthesis of medicinally relevant molecules,
as shown in Scheme 3. Doravirine is the active ingredient in
Pifeltro and the combination tablet Delstrigo recently ap-
proved by the FDA for the treatment of HIV. 1,3,5-Substi-
tuted arenes 29 and 30 containing multiple ortho-para di-
recting groups are intermediates in two different process-
scale routes to doravirine.17 Arenes with such substitution
patterns are well suited to being prepared by the silylation
of C-H bonds. A second medicinally relevant compound,
Ozenoxacin, is an antibiotic discovered by Toyama Chemical
Co., developed by Maruho Co,18 and approved in Japan for
the treatment of acne and skin infections. Heteroaryl bro-
mide 31 is an intermediate in the synthesis of Ozenoxacin.
Because electron-poor heteroarenes, such as 36, do not un-
dergo electrophilic aromatic bromination, C-H bond func-
tionalization is well suited to the synthesis of this class of
heteroarenes, vide supra. A third medicinally relevant com-
pound, AR-C123196, was produced on multikilogram scale
by AstraZeneca to furnish studies on its anti-inflammatory
properties and as a treatment for asthma.19 Hetero-biaryl
32 is an intermediate in the synthesis of AR-C123196 as-
sembled by Pd-catalyzed coupling of a heteroaryl bromide
and an arylboronic acid. The nucleophile and electrophile
can be reversed when C-H bond silylation is used because
the boronate for the coupling is generated from an aryl bro-
mide. In contrast, the heteroaryl silane can be used directly
as nucleophile, whereas the corresponding heteraryl-
boronic acid undergoes spontaneous proto-deboronation.
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Scheme 4. Synthesis of Doravirine Intermediatesa
substituted phenanthrolines, we measured kinetic isotope
1
effects for the silylation reactions of benzene and conducted
studies on H/D exchange between the silane and benzene
catalyzed by complexes of the series of phenanthrolines. To
probe if C-H bond cleavage was rate-limiting, we first meas-
ured the kinetic isotope effect for reactions of benzene in
separate vessels with catalysts containing 2,9-dimethyl,
2,4,7-trimethyl and 3,4,7,8-tetramethyl phenanthrolines
(ligands L1, L2, and L3). The initial rates were determined
by monitoring the silylarene product in the reactions cata-
lyzed by the combination of [Ir(COD)OMe]2 and ligand. As
shown in Table 4, the kinetic isotope effects were 1.3, 1.6
and 2.0 for the silylation of benzene and deuterobenzene
catalyzed by the combination of iridium and L1, L2, or L3
respectively with silane is the limiting reagent. Similar ki-
netic isotope effects of 1.6 or 1.7 were measured for the si-
lylation of benzene and deuterobenzene catalyzed by the
combination of iridium and L2, or L3 with arene as the lim-
iting reagent. These kinetic isotope effects are too small to
be considered simple primary values and more likely indi-
cate that cleavage of the C-H bond is fully or partially re-
versible.
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aSee SI for reaction conditions. Isolated yield is reported.
Yield determined by 1H NMR spectroscopy relative to CH2Br2
internal standard in parenthesis.
Table 4. Kinetic Isotope Effects Determined from Inde-
pendent Reactionsa
Heteroaryl bromide 31, an intermediate in the synthesis
of Ozenoxacin, was prepared in 68% yield by the combina-
tion of silylation of pyridine 36, with the catalyst containing
L1, followed by treatment with N-bromosuccinimide.
(Scheme 5). Although direct bromination of 36 is challeng-
ing, the ipso bromination of the silylheteroarene occurs un-
der mild conditions. Heterobiaryl 32, an intermediate in
AstraZeneca’s anti-inflammatory for asthma AR-C123196,
was prepared by silylation and coupling. Silylation of the
thienyl sulfonamide 37 occurred in quantitative yield, and
coupling of the resulting silylarene with 4-bromoanisole oc-
curred in the presence of catalytic amounts of Pd(PtBu3)2 to
produce 32 in 82% yield. In contrast to the reported insta-
bility of 5-boryl analogues of 37, the silylated heteroarene
was stable to chromatography and storage on the bench top.
These reaction sequences comprising silylation of a C-H
bond and functionalization at the C-Si bond demonstrate
that the system we report here for the silylation of C-H
bonds is useful for the synthesis of medicinally important
compounds.
aSee SI for conditions. Rates from reactions containing L1 de-
termined by GC-FID relative to dodecane internal standard.
1
Rates from reactions containing L2 and L3 determined by H
NMR spectroscopy relative to dodecane internal standard.
bArene (7.5 equiv), HSiMe(OTMS)2 (1 equiv). cArene (5.6
equiv), HSiMe(OTMS)2 (1 equiv). dArene (17 equiv),
HSiMe(OTMS)2 (1 equiv). eArene (1 equiv), HSiMe(OTMS)2 (1.4
f
equiv), average of three experiments (KIE = 1.6±0.3). Arene (1
Scheme 5. Synthesis of Ozenoxacin Intermediate and
AR-C123196 Intermediatea
equiv), HSiMe(OTMS)2 (1.4 equiv).
To gain further information about the potential reversi-
bility of the reaction, we studied H/D exchange between the
Si-H bond of the silane and deuterated arene. These data are
shown in Figure 3. H/D exchange between the silane and
benzene-d6 was evidenced by the growth of 1H NMR signals
of the arene. The rates at which the benzene-d6 was trans-
formed into benzene-d5 under the catalytic reaction condi-
tions with ligand L1 and with ligand L2 were measured. The
incorporation of protons into deuterated benzene catalyzed
by the combination of iridium and L1 was nearly five times
faster than that catalyzed by the combination of iridium and
L2. These relative rates closely mirror the five-times greater
rates for the silylation reaction catalyzed by the complex of
L1 than by the complex of L2.
aSee SI for reaction conditions. Isolated yield is reported.
5. Mechanistic Studies
To gain information on the steps of the catalytic process
influenced by the steric properties of the methyl-
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Figure 3. Rate of Protiation of Deuterobenzene Figure 4. Proposed Reaction Coordinate
Page 8 of 11
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0.16
0.14
0.12
0.1
d[pdt]/dt = 7.2•10-6
krel = 4.5
r2 = 0.97
L1
L2
Faster and thermodynamically more favorable oxidative
addition of a C-H bond to a more sterically hindered com-
plex seems counterintuitive in a system that is unlikely to
involve dissociation of the hindered ligand. We suggest that
the seven-coordinate product from oxidative addition,
counterintuitively, suffers less steric hindrance than the
starting square pyramidal complex. As shown in Figure 5,
seven coordinate complexes in a geometry like a capped
trigonal prism likely contain fewer ligands in the plane of
the substituted phenanthroline ligand. The five-coordinate
square-based pyramidal geometry of a d6 iridium-complex
contains two ligands in the equatorial plane (shown as the
plane of the page in Figure 5) in addition to the nitrogens of
the phenanthroline, whereas the seven-coordinate complex
contains just one additional ligand in the equatorial plane.
This model implies that the destabilization of the resting
state of the catalyst by the methyl groups of L1 is greater
than the destabilization of the intermediate following oxi-
dative addition. This analysis is consistent with our asser-
tion that the difference in energy between these two species
is responsible for the high rate of the silylation of aryl C-H
bonds observed in reactions catalyzed by the iridium com-
plexes containing the 2,9-dimethyl phenanthroline ligand.
0.08
0.06
0.04
0.02
0
d[pdt]/dt = 1.6•10-6
krel = 1
r2 = 1.0
0
1000
t (s)
aConditions: HSiMe(OTMS)2 (0.4 mmol), [Ir(cod)(OMe)]2
(1.0 mol %), ligand (2.0 mol %), dodecane (0.5 equiv), benzene-
d6 (100 µL), THF, 80 °C. Silylarene concentration was deter-
mined by H NMR spectroscopy using n-dodecane as an inter-
nal standard.
1
The faster rate of the silylation catalyzed by the complex
of L1 versus that of the silylation catalyzed by the complex
of L2 could result from faster cleavage of the C-H bond, a
more favorable equilibrium for cleavage of the C-H bond, or
larger effect of the ligand on the formation of the C-Si bond
than on the cleavage of the C-H bond. The small KIE value
observed for reactions of benzene and the observation of
H/D exchange between the silane and benzene imply that
cleavage of the C-H bond in benzene is reversible. In this
case, a difference in the equilibrium constant for cleavage of
the C-H bond or a difference in the rate of formation of the
C-Si bond could lead to the difference in rates of reaction
catalyzed by complexes of L1 and L2. The similarity be-
tween the difference in the rates of H/D exchange between
the silane and benzene catalyzed by the two complexes and
the difference in rates of the overall silylation of benzene
catalyzed by the two complexes implies that the cleavage of
the C-H bond is the step that leads to the difference in rates
of reaction of the two catalysts. These conclusions can be
shown in the reaction coordination diagram of Figure 4. In
this diagram, the rate and equilibrium constant for cleavage
of the C-H bond in the arene is larger for the reaction of the
complex of L1 than of the complex of L2, as suggested by
our mechanistic data.
Figure 5. Model for the Relief of Steric Upon Oxidative
Addition of C-H Bonds
Conclusion
In summary, we report an iridium catalyst for the silyla-
tion of arenes with hydrosilanes revealed by measuring the
difference between initial rates and overall conversion.
These measurements distinguished between catalysts that
react with low rates and those that react with high rates but
are short-lived. By determining the origin of inhibition of a
catalyst that reacts with high initial rates, we have devel-
oped the combination of a highly active catalyst and appro-
priate reaction conditions to achieve a large increase in
scope of the silylation of arenes and large increase in rates
for arenes that reacted with catalysts reported previously.
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Functionalization in organic synthesis. Chem. Soc. Rev. 2011, 40, 1855.
The new system tolerates most common functional groups,
(d) Gutekunst, W. R.; Baran, P. S. C-H functionalization logic in total
synthesis. Chem. Soc. Rev. 2011, 40, 1976. (e) McMurray, L.; O'Hara, F.;
Gaunt, M. J. Recent developments in natural product synthesis using
metal-catalysed C–H bond functionalisation. Chem. Soc. Rev. 2011, 40,
1885. (f) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond
Functionalization: Emerging Synthetic Tools for Natural Products and
Pharmaceuticals. Angew. Chem. Int. Ed. 2012, 51, 8960. (g) White, M. C.
Adding Aliphatic C–H Bond Oxidations to Synthesis. Science 2012, 335,
807. (h) Neufeldt, S. R.; Sanford, M. S. Controlling Site Selectivity in
Palladium-Catalyzed C–H Bond Functionalization. Acc. Chem. Res.
2012, 45, 936. (i) Wencel-Delord, J.; Glorius, F. C-H bond activation
enables the rapid construction and late-stage diversification of
functional molecules. Nat. Chem. 2013, 5, 369. (j) Cernak, T.; Dykstra,
K. D.; Tyagarajan, S.; Vachal, P.; Krska, S. W. The medicinal chemist's
toolbox for late stage functionalization of drug-like molecules. Chem.
Soc. Rev. 2016, 45, 546. (k) Wedi, P.; van Gemmeren, M. Arene-Limited
Nondirected C−H Activation of Arenes. Angew. Chem. Int. Ed. 2018, 57,
13016.
2. (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.;
Hartwig, J. F. C-H Activation for the Construction of C-B Bonds. Chem.
Rev. 2010, 110, 890. (b) Hartwig, J. F. Borylation and Silylation of C-H
Bonds: A Platform for Diverse C-H Bond Functionalizations. Acc. Chem.
Res. 2012, 45, 864. (c) Hartwig, J. F. Evolution of C–H Bond
Functionalization from Methane to Methodology. J. Am. Chem. Soc.
2016, 138, 2. (d) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous
C–H Bond Functionalization: Challenges and Opportunities. ACS Cent.
Sci. 2016, 2, 281.
3. (a) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R. I. C–H
activation/borylation/oxidation: A one-pot unified route to meta-
substituted phenols bearing ortho-/para-directing groups. J. Am. Chem.
Soc. 2003, 125, 7792. (b) Miyaura, N., Metal-Catalyzed Cross-Coupling
Reactions of Organoboron Compounds with Organic Halides. In Metal-
Catalyzed Cross-Coupling Reactions, de Meijere, A.; Diederich, F., Eds.
Wiley-VCH: Weinheim, 2004; Vol. 1, pp 41. (c) Tzschucke, C. C.;
Murphy, J. M.; Hartwig, J. F. Arenes to anilines and aryl ethers by
sequential iridium-catalyzed borylation and copper-catalyzed
coupling. Org. Lett. 2007, 9, 761. (d) Murphy, J. M.; Liao, X.; Hartwig, J.
F. Meta Halogenation of 1,3-Disubstituted Arenes via Iridium-
Catalyzed Arene Borylation. J. Am. Chem. Soc. 2007, 129, 15434. (e)
Liskey, C. W.; Liao, X.; Hartwig, J. F. Cyanation of Arenes via Iridium-
Catalyzed Borylation. J. Am. Chem. Soc. 2010, 132, 11389. (f) Partridge,
B. M.; Hartwig, J. F. Sterically Controlled Iodination of Arenes via
Iridium-Catalyzed C–H Borylation. Org. Lett. 2012, 15, 140. (g)
Robbins, D. W.; Hartwig, J. F. A C-H Borylation Approach to Suzuki-
Miyaura Coupling of Typically Unstable 2-Heteroaryl and
Polyfluorophenyl Boronates. Org. Lett. 2012, 14, 4266. (h) Litvinas, N.
1
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and the reactions occur with high sterically derived regiose-
lectivity. The products of these reactions can be trans-
formed into many common functional groups, and the util-
ity of this method was demonstrated by constructing inter-
mediates in the syntheses of medicinally important mole-
cules. This method significantly increases the utility of C-H
silylation by allowing reactions to be conducted on conven-
ient time-scales under mild conditions and with inexpen-
sive reagents.
9
Studies on isotopically labeled arenes showed that the
cleavage of the C-H bond is reversible. The relative rates of
H/D exchange catalyzed by complexes of 2,9-dimethylphe-
nanthroline and 2,4,7-trimethylphenanthroline mirrored
those of the initial rates of the silylation. These data imply
that the difference in activity observed for reactions of
arenes and silane with the two catalysts results from a dif-
ference in the equilibrium constant for addition of the arene
to the two catalysts. More favorable oxidative addition of
the arene to the complex of the more hindered ligand is
counterintuitive, but likely results from the difference in ge-
ometry of a five-coordinate square-planar d6 complex and a
seven-coordinate intermediate that would contain fewer
ligands in the plane of the phenanthroline ligand. Further
experimental mechanistic studies to prepare potential in-
termediates and detailed computational studies on the re-
activity of these intermediates to gain further insight in to
the mechanism and to create even more active catalysts are
in progress.
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ASSOCIATED CONTENT
Supporting Information. Experimental procedures, charac-
terization of new compounds, and spectroscopic data are pro-
vided in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
D.;
Fier, P. S.; Hartwig, J. F. A General Strategy for the
Corresponding Author
Perfluoroalkylation of Arenes and Arylbromides by Using Arylboronate
Esters and (phen)CuRF. Angew. Chem. Int. Ed. 2012, 51, 536. (i)
Robbins, D. W.; Hartwig, J. F. Sterically Controlled Alkylation of Arenes
through Iridium-Catalyzed C–H Borylation. Angew. Chem. Int. Ed. 2013,
52, 933. (j) Fier, P. S.; Luo, J.; Hartwig, J. F. Copper-Mediated
Fluorination of Arylboronate Esters. Identification of a Copper(III)
Fluoride Complex. J. Am. Chem. Soc. 2013, 135, 2552.
4. Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic
Methodologies on Medicinal Chemistry: Where Have All the New
Reactions Gone? J. Med. Chem. 2016, 59, 4443.
5. Brotherton, R. J.; McCloskey, A. L.; Boone, J. L.; Manasevit, H. M. The
Preparation and Properties of Some Tetraalkoxydiborons. J. Am. Chem.
Soc. 1960, 82, 6245.
6. Obligacion, J. V.; Chirik, P. J. Earth-abundant transition metal
catalysts for alkene hydrosilylation and hydroboration. Nat. Rev. Chem.
2018, 2, 15.
7. (a) Bracegirdle, S.; Anderson, E. A. Arylsilane oxidation—new routes
to hydroxylated aromatics. Chem. Commun. 2010, 46, 3454. (b) Nakao,
Y.; Hiyama, T. Silicon-based cross-coupling reaction: an
environmentally benign version. Chem. Soc. Rev. 2011, 40, 4893. (c)
Rayment, E. J.; Summerhill, N.; Anderson, E. A. Synthesis of Phenols via
Fluoride-free Oxidation of Arylsilanes and Arylmethoxysilanes. J. Org.
Chem. 2012, 77, 7052. (d) Denmark, S. E.; Ambrosi, A. Why You Really
Should Consider Using Palladium-Catalyzed Cross-Coupling of Silanols
and Silanolates. Org. Process Res. Dev. 2015, 19, 982. (e) Rayment, E. J.;
Mekareeya, A.; Summerhill, N.; Anderson, E. A. Mechanistic Study of
*jhartwig@berkeley.edu
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the NIH
(GM115812) (J.F.H.) for support. C.K. thanks Dr. Ala Bunescu
and Dr. Rhett Baillie for helpful discussions and Justin Wang for
assistance in the preparation of the manuscript. Z.C. thanks Dr.
Bo Su for helpful discussions on the functionalization of si-
lylarenes.
REFERENCES
1. (a) Godula, K.; Sames, D. C-H Bond Functionalization in Complex
Organic Synthesis. Science 2006, 312, 67. (b) Newhouse, T.; Baran, P.
S. If C–H Bonds Could Talk: Selective C–H Bond Oxidation. Angew. Chem.
Int. Ed. 2011, 50, 3362. (c) Davies, H. M. L.; Du Bois, J.; Yu, J.-Q. C-H
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
Arylsilane Oxidation through 19F NMR Spectroscopy. J. Am. Chem. Soc.
2017, 139, 6138.
8. Cheng, C.; Hartwig, J. F. Catalytic Silylation of Unactivated C–H Bonds.
Chem. Rev. 2015, 115, 8946.
9. (a) Ezbiansky, K.; Djurovich, P. I.; Laforest, M.; Sinning, D. J.; Zayes,
R.; Berry, D. H. Catalytic C-H Bond Functionalization - Synthesis of
Arylsilanes By Dehydrogenative Transfer Coupling of Arenes and
Triethylsilane. Organometallics 1998, 17, 1455. (b) Ishiyama, T.; Sato,
K.; Nishio, Y.; Miyaura, N. Direct synthesis of aryl halosilanes through
iridium(I)-catalyzed aromatic C-H silylation by disilanes. Angew. Chem.
Int. Ed. 2003, 42, p 5346. (c) Tsukada, N.; Hartwig, J. F. Intermolecular
11. Hongliu Liao; Renyuan Peng; Rongmei Lu; Xiao, S. Method for
synthesizing 1,1,1,3,5,5,5-heptamethyltrisiloxane by continuous
catalysis of solid phase catalyst. CN101921287B, 2010-12-22, 2012.
12. Cheng, C.; Hartwig, J. F. Rhodium-Catalyzed Intermolecular C-H
Silylation of Arenes with High Steric Regiocontrol. Science 2014, 343,
853.
1
2
3
4
5
6
7
8
13. Cheng, C.; Hartwig, J. F. Iridium-Catalyzed Silylation of Aryl C–H
Bonds. J. Am. Chem. Soc. 2015, 137, 592.
14. (a) Chotana, G. A.; Rak, M. A.; Smith, M. I. Sterically Directed
Functionalization of Aromatic C-H Bonds. Selective Borylation Ortho
to Cyano Groups in Arenes and Heterocycles. J. Am. Chem. Soc. 2005,
127, 10539. (b) Bisht, R.; Hoque, M. E.; Chattopadhyay, B. Amide Effects
in C−H Activation: Noncovalent Interactions with L-Shaped Ligand for
meta Borylation of Aromatic Amides. Angew. Chem. 2018, 130, 15988.
15. Morstein, J.; Kalkman, E. D.; Bold, C.; Cheng, C.; Hartwig, J. F.
Copper-Mediated C–N Coupling of Arylsilanes with Nitrogen
Nucleophiles. Org. Lett. 2016, 18, 5244.
16. Morstein, J.; Hou, H.; Cheng, C.; Hartwig, J. F. Trifluoromethylation
of Arylsilanes with [(phen)CuCF3]. Angew. Chem. Int. Ed. 2016, n/a.
17. (a) Campeau, L.-C.; Chen, Q.; Gauvreau, D.; Girardin, M.; Belyk, K.;
Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. A Robust
Kilo-Scale Synthesis of Doravirine. Org. Process Res. Dev. 2016, 20,
1476. (b) Deeks, E. D. Doravirine: First Global Approval. Drugs 2018,
78, 1643.
and
Intramolecular,
Platinum-Catalyzed,
Acceptorless
9
Dehydrogenative Coupling of Hydrosilanes with Aryl and Aliphatic
Methyl C-H Bonds. J. Am. Chem. Soc. 2005, 127, 5022. (d) Saiki, T.;
Nishio, Y.; Ishiyama, T.; Miyaura, N. Improvements of Efficiency and
Regioselectivity in the Iridium(I)-Catalyzed Aromatic C-H Silylation of
Arenes with Fluorodisilanes. Organometallics 2006, 25, 6068. (e)
Murata, M.; Fukuyama, N.; Wada, J.-i.; Watanabe, S.; Masuda, Y.
Platinum-catalyzed Aromatic C-H Silylation of Arenes with
1,1,1,3,5,5,5-Heptamethyltrisiloxane. Chem. Lett. 2007, 36, 910. (f)
Ishiyama, T.; Saiki, T.; Kishida, E.; Sasaki, I.; Ito, H.; Miyaura, N.
Aromatic C–H silylation of arenes with 1-hydrosilatrane catalyzed by
an iridium(i)/2,9-dimethylphenanthroline (dmphen) complex. Org.
Biomol. Chem. 2013, 11, 8162.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10. (a) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Chatani, N.; Murai, S.
Ruthenium-catalyzed dehydrogenative silylation of aryloxazolines
with hydrosilanes via C-H bond cleavage. Chem. Lett. 2001, 422. (b)
Tobisu, M.; Ano, Y.; Chatani, N. Rhodium-catalyzed silylation of
aromatic carbon-hydrogen bonds in 2-arylpyridines with disilane.
Chem. Asian J. 2008, 3, 1585. (c) Ihara, H.; Suginome, M. Easily
Attachable and Detachable ortho-Directing Agent for Arylboronic Acids
in Ruthenium-Catalyzed Aromatic C-H Silylation. J. Am. Chem. Soc.
2009, 131, 7502. (d) Choi, G.; Tsurugi, H.; Mashima, K. Hemilabile N-
Xylyl-N′-methylperimidine Carbene Iridium Complexes as Catalysts for
C–H Activation and Dehydrogenative Silylation: Dual Role of N-Xylyl
Moiety for ortho-C–H Bond Activation and Reductive Bond Cleavage. J.
Am. Chem. Soc. 2013, 135, 13149. (e) Kanyiva, K. S.; Kuninobu, Y.;
Kanai, M. Palladium-Catalyzed Direct C–H Silylation and Germanylation
of Benzamides and Carboxamides. Org. Lett. 2014, 16, 1968.
18. Flick, A. C.; Ding, H. X.; Leverett, C. A.; Kyne, R. E.; Liu, K. K. C.; Fink,
S. J.; O’Donnell, C. J. Synthetic Approaches to the New Drugs Approved
During 2015. J. Med. Chem. 2017, 60, 6480.
19. Allsop, G. L.; Cole, A. J.; Giles, M. E.; Merifield, E.; Noble, A. J.;
Pritchett, M. A.; Purdie, L. A.; Singleton, J. T. A Convergent Synthesis of
AR-C123196 Utilising Reaction Between a Cyclic Carbonate and a
Phenol for Aryl Alkyl Ether Formation. Org. Process Res. Dev. 2009, 13,
751.
20. Partridge, B. M.; Hartwig, J. F. Sterically Controlled Iodination of
Arenes via Iridium-Catalyzed C-H Borylation. Org. Lett. 2013, 15, 140.
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