Iridium-catalyzed silylation of aryl C-H bonds

Article abstract of DOI:10.1021/ja511352u

A method for the iridium-catalyzed silylation of aryl C-H bonds is described. The reaction of HSiMe(OSiMe₃)₂ with arenes and heteroarenes catalyzed by the combination of [Ir(cod)(OMe)]₂ and 2,4,7-trimethylphenanthroline occurs with the aromatic compound as the limiting reagent and with high levels of sterically derived regioselectivity. This new catalytic system occurs with a much higher tolerance for functional groups than the previously reported rhodium-catalyzed silylation of aryl C-H bonds and occurs with a wide range of heteroarenes. The silylarene products are suitable for further transformations, such as oxidation, halogenation, and cross-coupling. Late-stage functionalization of complex pharmaceutical compounds was demonstrated.

Full text of DOI:10.1021/ja511352u

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Silylation of Aryl C−H Bonds
Chen Cheng and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Scheme 1. Silylation of Aryl C−H Bonds
ABSTRACT: A method for the iridium-catalyzed silyla-
tion of aryl C−H bonds is described. The reaction of
HSiMe(OSiMe3)2 with arenes and heteroarenes catalyzed
by the combination of [Ir(cod)(OMe)]2 and 2,4,7-
trimethylphenanthroline occurs with the aromatic com-
pound as the limiting reagent and with high levels of
sterically derived regioselectivity. This new catalytic system
occurs with a much higher tolerance for functional groups
than the previously reported rhodium-catalyzed silylation
of aryl C−H bonds and occurs with a wide range of
heteroarenes. The silylarene products are suitable for
further transformations, such as oxidation, halogenation,
and cross-coupling. Late-stage functionalization of complex
pharmaceutical compounds was demonstrated.
ation, and amination reactions because the silane reagent is
activated by the two O-atoms connected to the Si.
However, two main drawbacks were evident from our studies
on the Rh-catalyzed silylation of aryl C−H bonds. First, the
reaction does nottolerate manyof the common functional groups
in medicinally important molecules, such as heavy halides,
carbonyl groups, and cyano groups; also, the reactions did not
occur at the C−H bonds of heteroarenes containing basic
nitrogen atoms. Reactions of aryl bromides and aryl iodides led
predominantly to protodehalogention of the carbon−halogen
bond, and reactions of arenes containing ketone and ester
functionalities led to hydrosilylation of the carbonyl groups
(Tertiary amides were tolerated, however.). Coordinating
groups, such as nitriles or pyridines, poisoned the catalyst.
Second, the chiral biaryl ligands in the Rh catalyst for arene
silylation are much more expensive than the bipyridine and
phenanthroline ligands in the Ir catalysts for arene borylation, and
the cost of the ligands can affect the utility of the reaction on a
large scale.
We report the discovery of an iridium precursor and
appropriately substituted phenanthroline ligand that catalyzes
the silylation of arenes and heteroarenes with high functional
group compatibility and high tolerance for basic heterocycles.
This reactivity enables the silylation reaction to form building
blocks for medicinal chemistry and to be used for the late-stage
functionalization of compounds with biological activity.
he functionalization of aryl and alkyl C−H bonds with main
T
group reagents, such as boranes and silanes, occurs with
unique regioselectivity dictated by the catalysts and provides
intermediates that can be derivatized to a wide range of products.
Prompted by initial observations of the borylation of arenes and
alkanes by isolated metal−boryl complexes,1 the catalytic
borylation of C−H bonds with Rh- and Ir-complexes has been
reported, including practical borylations of aryl C−H bonds.1c,2
The mechanism of these reactions has been revealed in detail,3
and applications of C−H borylation in the synthesis of several
complex molecules have been reported.4
Silanes are produced on a larger scale than boranes and can
serve as precursors to important commercial materials. More-
over, silanes can contain a broader combination of substituents
than boranes and, with the proper choice of substituents, can
generate valuable synthetic intermediates. However, the
silylation of aryl C−H bonds is less developed than the borylation
of aryl C−H bonds. Metal−silyl complexes are less reactive than
metal−boryl complexes toward C−H bond functionalization,
and most methods for the catalytic, intermolecular silylation of
aryl C−H bonds require high temperatures, a large excess of the
arene,5 or the presence of directing groups.6 Furthermore,
trialkylsilanes have been the most commonly used silane
reagent,5c,6b,d−f and the aryltrialkylsilane products formed from
reactions of these compounds have limited synthetic utility
because they undergo a narrower range of reactions than do
arylboron compounds.
To improve the functional group compatibility of the C−H
silylation of arenes, we investigated Ir catalysts that might
translate the high functional group compatibility of the Ir-
catalyzed borylation reactions to the silylation of arenes and
heteroarenes. To do so, we conducted silylations catalyzed by the
combination of an Ir(I) precursor and various bidentate N-based
ligands commonly used for the borylation of aryl C−H
bonds.1c,4c This combination of catalyst components has been
reported to induce the silylation of aryl C−H bonds with several
Recently, our group reported a Rh system that catalyzes
undirected, intermolecular silylation of aryl C−H bonds (Scheme
1).7 These reactions occurred with the inexpensive HSiMe-
(OSiMe3)2 as the Si source and with arene as the limiting reagent
under mild conditions (45 °C). In addition, the arylsilane
products are amenable to cross-coupling, oxidation, halogen-
Received: November 4, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja511352u
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Journal of the American Chemical Society
Communication
Scheme 2. Dehydrogenative Silylation of Alkenes with
Me4Phen and 2-MePhen as the Ligand9
Table 1. Evaluation of Reaction Conditions
a
ab
,
a
entry
ligand
conversion (%)
yield (%)
1a:1b
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
L3
L3
29
6
26
0
19:1
−
26:1
26:1
24:1
20:1
6:1
tetrafluorodisilanes, but the reactions were conducted with either
neat arene or 10 equiv of arene.5a,b
38
39
34
9
36
35
30
7
To test the activity of Ir catalysts for the silylation of arenes, we
conducted the reactions of 1 equiv of m-xylene with 1.5 equiv of
HSiMe(OSiMe3)2 at 80 °C inTHF with a catalyst generated from
[Ir(cod)OMe]2 and 3,4,7,8-tetramethyl-1,10-phenanthroline
(Me4Phen). Although this ligand leads to the most active current
catalyst for the borylation of aryl and alkyl C−H bonds,4c,8 the
corresponding silylxylene was obtained in only 10% yield, as
determined by GC. This result implied that a different ligand was
necessary for the silylation of arenes with broad scope.
22
31
45
53
93
19
0
−
38
49
90
11:1
26:1
25:1
c
10
cd
,
11
a
b
c
Determined by GC. Combined yield of 1a and 1b. Reaction run
with 1 equiv of cyclohexene. Reaction run at 100 °C.
d
Several considerations pointed to a catalyst for the silylation of
arenes in a synthetically valuable fashion. First, during our studies
on the dehydrogenative silylation of alkenes,9 we conducted
reactions with a series of 2-substituted phenanthroline ligands
and found that reactions catalyzed by complexes of 2-methyl-
1,10-phenanthroline (2-MePhen, L1) generated a significant
amount of product from dehydrogenative silylation of
norbornene (Scheme 2). The dehydrogenative silylation of
terminal alkenes catalyzed by complexes of Me4Phen (L2)
generated only the desired alkene silylation product and the
hydrogenation byproduct norbornane. According to 2H-labeling
experiments, the silylation of terminal alkenes occurs by syn-
insertion and syn-β-H elimination.9 However, this mechanism
would not lead to the dehydrogenative silylation of norbornene
because the fused-ring structure would inhibit the β-H
elimination. Thus, the silylation of norbornene likely occurred
by direct C−H activation. This logic led us to consider that 2-
substituted phenanthrolines could generate a more active silyl
complex for the activation of C(sp2)−H bonds than would
Me4Phen.
Second, the functionalization of arenes with boron reagents
occurs faster with electron-poor arenes than it does with electron-
rich arenes.2c Thus, we studied the silylation of 3-tolunitrile as a
model substrate. This substrate is a suitable test of the method for
several reasons. First, the nitrile group in this substrate, which can
coordinate to the metal center, completely suppressed the Rh
catalyst for the C−H silylation.7 Second, because the nitrile group
contains unsaturation, this substrate would test the chemo-
selectivity of the catalyst toward C−H silylation vs hydro-
silylation. Third, this substrate would test whether the
regioselectivity is controlled by steric, electronic, or directing
effects because the nitrile is small and strongly electron
withdrawing and can serve as an ortho-directing group.10 Finally,
most functionalized arenes and basic heteroarenes are more
electron deficient than benzene; thus, an arene containing an
electron-withdrawing group could be a more appropriate model
for an arene in a medicinally active compound than would m-
xylene.
We evaluated the reaction of 3-tolunitrile with catalysts ligated
by a series of phenanthroline ligands containing 2-substituents
(Table 1). Reaction with 2-MePhen (L1) as the ligand at 80 °C in
THF for 16 h afforded the products (1a and 1b) from C−H
silylation in 26% yield. Surprisingly, the silylation of 3-tolunitrile
with Me4Phen (L2) as the ligand did not give any desired
product, even though reaction of m-xylene under similar
conditions with L2 formed the corresponding silylxylene in
10% yield. Varying the electronic property on the position para to
the nitrogen atoms led to a small increase in yields (L3−L5), the
highest yield obtained with 2,4,7-trimethyl-1,10-phenanthroline
(L3) as the ligand. Varying the substituent at the 2-position led to
lower yields (L6−L8) of the arylsilane product. Except for the
reaction with L8 as the ligand, the yields were similar to the
conversions.11 The silylation reaction catalyzed by Ir-L3 run with
a hydrogen acceptor occurred in slightly higher yields than
reactions without an acceptor (entry 10). Finally, the reaction
conducted at 100 °C occurred to high conversion and afforded 1a
and 1b in 90% yield (entry 11). Reactions conducted with other
hydrosilanes containing at least one alkoxy group connected to
silicon did not generate significant amounts of desired products
(see the Supporting Information (SI)).
After establishing these conditions for the Ir-catalyzed
silylation of arenes, we evaluated the functional-group compat-
ibility of this process. The tolerance of the reaction for auxiliary
functional groups is striking. The arene silylation is compatible
with ester, ketone, bromide, iodide, nitrile, and sulfone
functionalities (Scheme 3). Hydrosilylation of ketones and esters
was not observed, and the product of protodehalogenation of an
aryl iodide was observed in only 3% yield (7). In addition, the
reaction proceeded with high levels of sterically derived
regioselectivity. Various 1,3-disubstituted arenes underwent
silylation exclusively at the mutually meta positions, except for
3-CF3-anisole and 3-tolunitrile, which each afforded 4% of the
product in which the silyl group was installed ortho to the
relatively small OMe (6) and CN (1) groups. These results are
B
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Journal of the American Chemical Society
Communication
a
a
Scheme 3. C−H Silylation of Arenes
Scheme 5. C−H Silylation of Pharmaceutical Compounds
a
Yields of isolated products. b3% of inseparable protodeiodination
product was also obtained.
a
Scheme 4. C−H Silylation of Heteroarenes
a
Reactions conducted under conditions similar to the conditions in
Scheme 3. For detailed procedures, see the SI. Yields of isolated
products reported.
the C−H bond α to the basic nitrogen. Silylation of an
unhindered pyridine, 3-picoline (24), required high temperature
(120 °C), but formed the product in an acceptable 59% yield. The
slow rate likely results from strong binding of the substrate to the
metal center through the basic N-atom.
The conditions for the silylation of simple arenes were suitable
for the functionalization of the active pharmaceutical ingredients
(APIs) in some of the most prescribed drugs (Scheme 5),15,16
indicating that the scope of the reaction is appropriate for
applications in medicinal chemistry. Moreover, these reactions
reveal the relative reactivity of different types of aryl and
heteroaryl C−H bonds. For example, the silylation of clopidogrel,
duloxetine, and ketotifen all occurred selectively at the 2-position
of the thiophene moiety over the benzene or naphthalene ring
(25−27). Silylation of the pyridine ring in mirtazapine also
occurred over silylation of the benzene ring, although 14% of
readily separable disilylation products were also obtained (28). In
addition, the secondary alkyl amine moieties in duloxetine (26)
and desloratadine (29) were protected in situ by silylation of the
N−H bond and did not interfere with subsequent silylation of
C−H bonds.17 In contrast to this reactivity, the C−H borylation
does not occur in the presence of secondary alkylamines.
Furthermore, the imidazoline moiety in clonidine (31), the
secondary amide in aripiprazole (33), and the imides in
thalidomide (30) were all tolerated, and single isomers of the
silylation products were obtained from these substrates because
of the relative accessibility of the various C−H bonds.
Because of the presence of the Si−O bonds in the silyl
substituent, the silylarene products are suitable for trans-
formations that form C−heteroatom and C−C bonds, such as
oxidations,18 halogenations, and cross-couplings.19 As shown in
Scheme 6, reactions of both simple arenes and products from the
silylation of APIs occurred to form the corresponding phenols,
aryl halides, and biaryls in good isolated yields. The suitability of
the methods for functionalization of aryl−Si bonds in several
polycylic arylsilanes containing basic heterocycles and potentially
reactive functionality (41, 44, 45) illustrates the suitability of
a
Reactions conducted under conditions similar to the conditions in
Scheme 3. For detailed procedures, see the SI. Yields of isolated
products reported. Reaction conducted at 120 °C for 2 d.
b
comparable to the results from borylation of 3-CF3-anisole and 3-
tolunitrile, in which 3% and 6% of the products containing the
boryl group ortho to the OMe and CN group formed,
respectively.12
The compatibility with heteroarenes, especially those contain-
ing basic nitrogen atoms, was also striking. Silylation of
potentially coordinating pyrazines, pyrimidines, and azaindoles
afforded the corresponding silylarenes in good yields (Scheme 4).
Reaction of five-membered heteroarenes required lower temper-
atures than reactions of pyrimidines and pyrazines and proceeded
with high levels of regioselectivity for functionalization of the C−
H bonds α to the heteroatoms. Silylation of heteroarenes in
which the α-positions are substituted (23) or sterically hindered
because of a large substituent on the nitrogen (22) occurred at
the β-positions. Silylation of the free NH group of 7-
methoxyindole (17) and of pyrrole (20) did not occur under
the reaction conditions. However, silylation of unprotected
azaindoles first occurred at the N−H bond (16).13,4c,14
Subsequent silylation at the sterically accessible C−H bond β
to the pyridine nitrogen and hydrolysis of the N−Si bond
furnished a single product from C−H silylation. Like the
borylation of heteroarenes containing basic N-atoms,2e,4c the
silylation occurred at the C−H bond β to the basic nitrogen over
C
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Journal of the American Chemical Society
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a
Scheme 6. Functionalization of Silylarene Products
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1213409) for funding and the LBNL/
UC-Berkeley Catalysis Program Instrumentation Facility (DOE,
KC0302010) for the use of an HPLC instrument.
REFERENCES
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silylation and subsequent derivatization for the late-stage
functionalization of complex molecules.
In summary, we have developed a method for the
intermolecular C−H silylation of arenes that occurs with the
arene as the limiting reagent and exhibits high levels of sterically
derived regioselectivity. Compared to the Rh-catalyzed silylation
of an aryl C−H bond, this Ir-catalyzed C−H silylation is
compatible with a much broader scope of functional groups and
occurs with a broader range of heteroarenes, making it
particularly suitable for late-stage functionalization of complex
pharmaceutical molecules. However, the reaction requires higher
temperatures than the Rh-catalyzed silylation or the C−H
borylation, and the regioselectivity of reactions with unsym-
metrical 1,2-disubstituted arenes is lower (see the SI). Moreover,
the range of reactions of the arylsilanes is narrower than that of
aryl boronic esters. Thus, efforts to identify ligands that increase
the rate and the regioselectivity of the process, along with
methods for further functionalization of the silylarene products,
are goals of future studies in our laboratory.
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(11) Reaction conducted with L8 as the ligand led to mainly
hydrosilylation of the nitrile group.
(12) The borylation reactions were conducted following the literature
procedures (ref 1c).
(13) The difference among the reactivity of the N−H bonds in
azaindoles, pyrroles, and indoles under the silylation conditions is similar
to their reactivity under the borylation conditions (refs 4c and 14). For
possible causes, see ref 4c.
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ASSOCIATED CONTENT
■
S
* Supporting Information
(15) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
2010, 87, 1348.
Detailed experimental procedures and characterization of
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
(16) Top 100 Most Prescribed, Top Selling Drugs. http://www.
medscape.com/viewarticle/825053 (accessed Oct 2014).
(17) The secondary amine moiety in bupropion was not silylated
during the reaction, presumably because of the steric hindrance of the
tert-butyl group (31).
AUTHOR INFORMATION
■
Corresponding Author
(18) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694.
jhartwig@berkeley.edu
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(b) Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/ja511352u
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX