Iridium-Catalyzed Silylation of Five-Membered Heteroarenes: High Sterically Derived Selectivity from a Pyridyl-Imidazoline Ligand

Article abstract of DOI:10.1002/anie.201916015

The steric effects of substituents on five-membered rings are less pronounced than those on six-membered rings because of the difference in bond angles. Thus, the regioselectivities of reactions of five-membered heteroarenes that occur with selectivities dictated by steric effects, such as the borylation of C?H bonds, have been poor in many cases. We report that the silylation of five-membered-ring heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination of [Ir(cod)(OMe)]₂ (cod=1,5-cyclooctadiene) and a phenanthroline ligand or a new pyridyl-imidazoline ligand that further increases the regioselectivity. The silylation reactions with these catalysts produce high yields of heteroarylsilanes from functionalization at the most sterically accessible C?H bonds of these rings under conditions that the borylation of C?H bonds with previously reported catalysts formed mixtures of products or products that are unstable. The heteroarylsilane products undergo cross-coupling reactions and substitution reactions with ipso selectivity to generate heteroarenes that bear halogen, aryl, and perfluoroalkyl substituents.

Full text of DOI:10.1002/anie.201916015

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Iridium-Catalyzed Silylation of Five-Membered Heteroarenes:
High Sterically Derived Selectivity from a Pyridyl-Imidazoline
Ligand
Authors: Caleb Karmel, Camille Z. Rubel, Elena V. Kharitonova, and
John F. Hartwig
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201916015
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10.1002/anie.201916015
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RESEARCH ARTICLE
Iridium-Catalyzed Silylation of Five-Membered Heteroarenes:
High Sterically Derived Selectivity from a Pyridyl-Imidazoline
Ligand
Caleb Karmel‡, Camille Z. Rubel‡, Elena V. Kharitonova‡, and John F. Hartwig*[a]
[a]
Department of Chemistry,
University of California, Berkeley, CA, 94720 USA
jhartwig@berkeley.edu
These authors contributed equally.
[‡]
Supporting information for this article is given via a link at the end of the document.
Abstract: The steric effects of substituents on five-membered rings
are less pronounced than those on six-membered rings because of
the difference in bond angles. Thus, the regioselectivities of reactions
that occur with selectivities dictated by steric effects, such as the
borylation of C-H bonds, have been poor in many cases. We report
that the silylation of five-membered ring heteroarenes occurs with high
sterically derived regioselectivity when catalyzed by the combination
of [Ir(cod)(OMe)]2 and a phenanthroline ligand or a new pyridyl-
imidazoline ligand that further increases the regioselectivity. The
silylation reactions with these catalysts produce high yields of
heteroarylsilanes from functionalization at the most sterically
accessible C–H bonds of these rings under conditions that the
borylation of C–H bonds with previously reported catalysts formed
mixtures of products or products that are unstable. The
heteroarylsilane products undergo cross-coupling reactions and
substitution reactions with ipso selectivity to generate heteroarenes
that bear halogen, aryl and perfluoroalkyl substituents.
of the arene; these catalysts selectively functionalize C–H bonds
that are distal to functional groups in preference to C-H bonds that
are more acidic, but proximal to functional groups. Thus,
symmetrical 1,2-disubstituted or unsymmetrical 1,3-disubstituted
or 1,2,3-trisubstituted arenes undergo borylation at the C–H meta
to the nearest substituent (Figure 1).
Introduction
The application of C-H bond functionalization to synthetic
chemistry requires the selective activation of a single C–H bond
among multiple C–H bonds that possess different steric and
electronic properties.[1], [2] A common strategy for controlling the
selectivity of catalytic reactions that functionalize the C–H bonds
of arenes is to incorporate a functional group on the arene that
coordinates to a transition-metal catalyst and directs the reaction
to C–H bonds that are ortho, meta or para to that functional
group.[3]
Undirected functionalizations of the C–H bonds of arenes
occur with selectivities that are determined by the steric and
electronic properties of the various types of C–H bonds.[4] The
most classical undirected functionalizations include uncatalyzed
or Lewis-acid catalyzed electrophilic aromatic substitution (EAS)
processes. In general, these reactions occur at the most electron-
rich C–H bonds, and the steric properties of the groups impart a
secondary influence on selectivity.[5]
Figure 1. EDG
withdrawing functional group LB = Lewis basic functional group.
= Electron donating functional group. EWG = electron
The regioselectivity of the functionalization of heteroarenes
is more complex than that of 6-membered rings because the more
acute bond angles in 5-membered rings cause the distances
between the substituents to be longer than those in 6-membered
rings. This difference in distances between substituents in 5- and
6-membered rings makes the influence of steric properties on the
selectivity of the functionalization of 5-membered heteroarenes
less pronounced (Figure 1). Thus, catalytic functionalization of a
single C–H bond in a five-membered ring heteroarene with high
regioselectivity derived from steric effects is rare due to the
distinct electronic properties of the positions of heteroarenes and
the weaker steric influence in five-membered ring structures.
Consistent with this trend, the functionalization of these
rings is limited by the poor selectivity of iridium-catalyzed
borylation reaction, the low activity of catalysts for silylation
reactions, and the requirement of special reagents for silylation.
In particular, the current borylations of five-membered
heteroarenes, in many cases, form isomers from the
In contrast, the silylations and borylations of the C–H bonds
of arenes catalyzed by iridium complexes of bipyridine or
phenanthroline ligands generally occur at the most sterically
accessible and acidic C–H bonds.[6] The regioselectivity of these
reactions is almost exclusively determined by the steric properties
1
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functionalization of sites ortho to small or medium-sized
substitutents and product from diborylation,[7] even with the
recently developed catalyst of Smith and Maleczka that contains
a novel N-N ligand and with excess of thiophene.[8] Iridium-
catalyzed silylations of these rings reported by Ishiyama and
Miyaura with a phenanthroline bearing a large substituent in the
2-position occurred with several 3-substituted thiophenes and one
furan with high sterically derived regioselectivity, but the low
activity of this catalyst caused the reactions to require a large
excess of heteroarene and high temperatures, and the tetrafluoro
disilane used in this process is not commercially available and
requires three steps to prepare.[9] Finally, neither the work of
Ishiyama nor Smith describes the functionalization of
heteroarenes containing multiple heteroatoms, even though these
structures are among the most prevalent heteroarenes in
medicinal and agrochemical chemistry.[10]
To create a benchmark for our studies on the silylation of
five-membered ring heteroarenes, we first measured the yield and
selectivity of the borylation of 3-chlorothiophene that was
catalyzed by the previously reported combination of
[Ir(COD)(OMe)]2 and 4,4’-di-tert-butylbipyridine (dtbpy).[19] Under
standard conditions, the products from functionalization at
positions both proximal and distal to the chlorine substituent
formed, and the major product resulted from diborylation (Scheme
1). Similarly, the silylation of 3-chlorothiophene under the
conditions recently reported by our group with 2,9-
dimethylphenanthroline as ligand formed a mixture of products
from silylation at both the 2 and 5-positions.
In contrast, the silylation of 3-chlorothiophene that was
catalyzed by the combination of [Ir(COD)(OMe)]2 and L2 was
selective for functionalization at the 5-position of the heteroarene.
This regioselectivity was even higher when the reaction was
catalyzed by [Ir(COD)(OMe)]2 and the imidazoline ligand L3 and
was the highest when catalyzed by [Ir(COD)(OMe)]2 and
imidazoline ligand L4, which contains a 2,6-iPr-phenyl group on
the imidazoline nitrogen. The silylation of 3-chlorothiophene,
when catalyzed by iridium and L3, formed the product from
functionalization at the 5-position in 74% yield, and the silylation
of this thiophene, when catalyzed by iridium and L4, formed the
product from functionalization at the 5-position in 90% yield with
a 9:1 selectivity for this isomer over others and the product from
di-functionalization.
The identification of reactions that functionalize C-H bonds
in five-membered-ring heteroarenes containing one or multiple
heteroatoms regioselectively is important because these
structural motifs are common in pharmaceuticals, electronic
materials, agrochemicals, and natural products.[11] The
regioselective silylation and borylation of heteroarenes would be
particularly useful because silylarenes and aryl boronic esters
undergo
hydroxylation,[12]
etherification,[13]
amination,[14]
cyanation,[15] halogenation,[16] and arylation,[17] and analogous
derivatization of heteroarenes would provide an array of
heteroarenes with substitution patterns that are derived from the
catalytic system. The silylation of heteroarenes can be particularly
valuable because the heteroarylsilanes are often more stable
than the corresponding heteroarylboronates.[18]
Scheme 1. Effect of Ligand on Selectivitya
We report silylations of five-membered heteroarenes
catalyzed by an iridium complex that contains a pyridyl-
imidazoline ligand, and also silylations catalyzed by a recently
disclosed complex of 2,9-Me2-phenanthroline (Me2phen). We
demonstrate that reactions with these catalysts produce high
yields of products that are formed from functionalization of the
most sterically accessible C–H bonds of five-membered
heteroarenes under conditions in which borylation reactions
produce mixtures of products. We also illustrate the versatility of
the heteroarylsilanes by developing conditions for ipso
substitution reactions to produce the corresponding five-
membered-ring heteroarenes bearing halogen, aryl and
perfluoroalkyl substituents.
Results and Discussion
aSee SI for detailed procedures
1. Reaction Development
To achieve the undirected functionalization of five-
membered heteroarenes with regioselectivity that is dictated by
steric effects, we investigated reactions catalyzed by iridium
complexes of a series of ligands that contain nitrogen donors. Two
of the ligands, L1 and L2, are based on pyridyl oxazoline
structures, and two of the ligands, L3 and L4, are based on pyridyl
imidazoline structures. Ligand L4 is new, and none of the ligands
have been reported for the borylation or silylation of aromatic C–
H bonds. We included pyridyl imidazoline structures in our study
because the nitrogen atoms should be more electron donating
than those in the pyridyl oxazoline structures, and substituents on
the nitrogen in the imidazoline could influence the structures of
these ligands.
We note that this regioselectivity for silylation and
chemoselectivity for monosilylation is obtained with limiting
heteroarene. The regioselectivity is similar to that reported for the
borylation or silylation of the same substrate, but our silylation
reaction occurs with the thiophene as limiting reagent. The results
on borylation or silylation were obtained with an excess of
thiophene, and high selectivity for mono-borylation of such a
thiophene with the heteroarene as limiting reagent has not been
reported with any catalyst.[8-9]
2. Reaction Scope
Having identified a ligand that greatly increases the
sensitivity of the iridium-catalyzed silylation of thiophenes to the
2
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10.1002/anie.201916015
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RESEARCH ARTICLE
steric environment of the C–H bonds, we studied the selectivity of
this catalyst for the silylation of thiophenes that contain varied
functional groups. We conducted silylation reactions with the
catalyst that contains L4 and cyclohexene as hydrogen acceptor,
silylations with the catalyst that contains Me2Phen and
norbornene as hydrogen acceptor, and borylations with the
catalyst that contains dtbpy (Scheme 2) without any hydrogen
acceptor. These combinations of catalyst and acceptor for the
silylations were used because the yields of silyl arenes from
reactions conducted with the catalyst that contains Me2Phen and
cyclohexene were low, and only traces of silyl arenes were
detected from reactions conducted with L4 and norbornene.[19c] 5-
Results from the silylations catalyzed by the complex of
Me2Phen and the borylations catalyzed by the complex of dtbpy
in Scheme 2 show the value of the silylation of the catalyst that
contains L4 for obtaining high regioselectivity. The silylation of
thiophenes that contain smaller substituents occurred with low
selectivity for functionalization at the 5-position (1, 6, 7) when
catalyzed by the combination of iridium and Me2phen. The
borylations of these heteroarenes with iridium and dtbpy also
produced mixtures of products. Silylations of thiophenes that
contain larger phenyl, boryl, ester, bromide, and iodide
substituents (3-5, 8, 9) and that were catalyzed by iridium and
Me2phen occurred with complete selectivity for functionalization
Silyl-thiophenes that contain methyl, methoxy, phenyl, ester, boryl, at the 5-position of the heteroarene, but the yields were much
bromide and iodide substituents in the 3-position were obtained
with perfect selectivity for the monosilylation product, with perfect
regioselectivity, and in yields ranging from 44% to 100% from
reactions catalyzed by the combination of iridium and L4. The
ethyl ester of 5 and the nitrile of 6 were tolerated; no products from
reduction of these functional groups were observed. Thiophene 6,
which contains a small cyano substituent, was converted to the
lower than those catalyzed by iridium and L4. Likewise, borylation
with dtbpy was highly selective for the 5-position of 3-
phenylthiophene and ethyl 3-thiophenecarboxylate. However, the
borylation of all the other thiophenes in Scheme 2 occurred with
low selectivity for the 5-position. These results demonstrate that
the catalyst formed from the combination of iridium and L4 is more
active and more selective for the functionalization of the least
sterically hindered position of thiophenes than previously reported
catalysts.
corresponding
silylarene
with
85:12:3
selectivity
for
functionalization at the 5-position of 3-cyanothiophene to
functionalization at the 2-position to di-silylation. Likewise,
heteroarylsilanes that contain halogen substituents were obtained
from the corresponding arenes (7-9) in moderate (3-iodo) to high
(3-bromo and 3-chloro) yield and without proto-dehalogenation.
The reactions of the larger of the three halides gave a single
product; the reactions of the 3-chloro isomer gave 94:1
regioselectivity and 95:5 selectivity of monosilylation to disilylation.
Scheme 3. C-H Silylation of Furans and Pyrrolesa
Condition 1 (C1):
L4
3% Ir/
1.2 equiv HSiMe(OTMS)2,
1 equiv cyclohexene
Condition 2 (C2):
3% Ir/Me2phen,
1.2 equiv HSiMe(OTMS)2,
1 equiv norbornene
Scheme 2. C-H Silylation of Thiophenesa
Condition 3 (C3):
3% Ir/dtbpy,
0.6 equiv B2pin2
R
R
[E] [E]
= SiMe(OTMS)2
or Bpin
THF, 65-100 °C, 16-20 h
iPr
X
X
tBu
tBu
R
N
R =
iBu
N
N
N
N
N
N
iPr
Me
Me
O
Me
Ph
L4
Me2phen
dtbpy
Br
Bpin
H
H
H
O
O
b
10 C1
11 C1
12 C1
,
: 86% (82:14:4)
,
: 100%
,
: 100%
b
C2
C3
C2
C3
C2
C3
: 30% (34:46:20)
: 99%
: 100%
b
: 41% (55:8:37)
: 87% (90:0:10)
: 18% (19:6:75)
EtO2C
CyHNOC
MeO2C
H
H
H
O
O
N
H
13 C1
,
14 C1
15 C1
,
: 83%
,
: 60%
: 90%
C2
C3
C2
C3
C2
C3
: 53% (78:0:22)
: 17% (34:4:62)
: 43%
: 48% (75:18:7)
: 64% (76:16:8)
: 48% (64:36:0)
aSee SI for detailed procedures. Yields correspond to 1H NMR yield of desired
product (desired product : undesired, mono- : undesired, di-). b4 °C, 5 d.
The analogous silylation and borylation reactions of furans
and pyrroles are shown in Scheme 3. The silylations of 3-
substituted furans and pyrroles catalyzed by iridium and
imidazoline ligand L4 occurred with perfect selectivity and in good
yield (11-15, 60% to 100% yield). The silylation of 3-bromofuran
(10) occurred with greater than 80% selectivity for the 5-position.
In contrast, the silylation or borylation of 3-bromofuran under
previously reported conditions led to the formation of large
amounts of products from functionalization at the 2-position. In
aSee SI for detailed procedures. Yields correspond to 1H NMR yield of desired
product (desired product : undesired, mono- : undesired, di-)
3
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aSee SI for detailed procedures. Yields correspond to 1H NMR yield of desired
product (desired product : undesired, mono- : undesired, di-), [yield after
filtration through silica]. b5% Ir/L and 2 equiv. HSiMe(OTMS)2.
addition, the silylations of furans or pyrroles that contain esters at
the 3-positions produced significant amounts of products from
functionalization at the 2-position when the catalyst contained
Me2phen. The borylations of these nitrogen or oxygen-containing
heterocycles occurred with universally poor selectivity for the
least sterically hindered C–H bonds.
Five-membered ring heterocycles that contain multiple
heteroatoms also underwent silylation in good yield and with high
selectivity (Scheme 4). In these cases, the reactions occurred in
the highest yields when catalyzed by [Ir(COD)(OMe)]2 and
Me2phen. In all cases, the regioselectivity with which the silyl-
azole products formed was high. The regioselectivity was dictated
by steric effects with electronic effects influencing selectivity when
potentially reactive C–H bonds were present in similar steric
environments.
Three examples of the silylation of pyrazoles are provided
in Scheme 4. The reactions of 1,3-dimethylpyrazole 16, in which
the two aromatic C–H bonds are in similar steric environments
was completely selective for the 5-position, and this selectivity
was consistent with the high preference for functionalization α to
heteroatoms observed for the functionalization of thiophenes,
furans and pyrroles. However, the silylation of pyrazoles that
contain larger tert-butyl carbonate or tosyl substituents on
nitrogen occurred distal to the nitrogen that bears that substituent.
These results indicate that the silylation of pyrazoles occurs with
a selectivity that is determined primarily by the steric environment
of the C–H bonds, with electronic effects imparting a secondary
influence.
The silylations of the thiazoles occurred at the position that
is most sterically accessible. One might expect that the reaction
would occur at the position more distal to the basic nitrogen
because borylations of pyridines were shown previously not to
form products from reaction at the position alpha to a basic
nitrogen atom.[20] However, the silylation reaction formed a stable
product from reaction at the 2-position of 4-substituted thiazoles
due to the steric congestion at the 5-position, even if the
substituent at the 4-position was as small as a methyl group.
The silylations of heteorarenes containing multiple nitrogen
atoms also formed stable products in good yield. The silylation of
imidazole 21 containing substituents at the 1 and 2 positions gave
a single product from reaction at the 4 position. The imidazole unit
of caffeine gave a stable product from reaction at the only
available aromatic C–H bond. Silylation of the 1,2,3- and 1,2,4-
triazoles also occurred at the sterically more accessible of the two
heteroaryl C–H bonds to form stable products albeit with 5 mol %
catalyst.
The borylations of 16, 18 and 21-23 occurred with high
selectivity to form the products indicated in Scheme 4, but the
borylated products were unstable. The borylations of 16-18, 21,
and 22 gave the functionalized product in only 37-74% yields, and
reactions of 19, 20, and 24 gave no borylated product, as
determined by evaluating the crude reaction mixtures. Moreover,
the amounts of borylated products from the reactions of 16 and
18 were lower after the reaction mixtures were filtered through
silica, and no borylated products were present from reactions of
21, 22 and 23 after the reaction mixtures were filtered through
silica. Thus, consistent with prior literature, the products from the
borylation of azoles are, in many cases, unstable to air and, in
most cases, unstable to silica.[18, 20] In contrast, the products from
the silylation of azoles 16-23 were isolated by silica gel
chromatography, and the largest difference in yield of isolated
silyl-azole products and yield determined from the crude reaction
mixture was only 12%. The silyl-azole products are stable to air,
moisture from solvents stored on the benchtop, and silica. The
greater stability of silyl-azoles than of boryl-azoles renders the
silylation of the C–H bonds of azoles particularly useful.
Scheme 4. C-H Silylation of Azolesa
3. Functionalization of Heteroarylsilanes
To demonstrate the utility of C–H silylation to the
preparation of functionalized heteroarenes, we assessed the
ability to convert the silyl heteroarenes to heteroarenes that are
functionalized with halogens or with aryl or trifluoromethyl groups
(Scheme 5, right). In addition, we compared the products one
would obtain from the combination of silylation and
functionalization to those from more classical processes (Scheme
5, left). The silylation of ethyl 3-furan carboxylate, followed by
functionalization with N-chlorosuccinimide in the presence of AgF
formed ethyl 2-chloro-4-furancarboxylate 25 in 63% yield over two
steps. In contrast, directed metalation of the related 3-
furancarboxylate, followed by quenching with hexachloroethane,
is known to produce 2-chloro-3-furancarboxylate.[21] The silylation
of 3-chlorothiophene, followed by functionalization with N-
bromosuccinimide and AgF, formed bromide 2-bromo-4-
chlorothiophene 26 in 72% yield over two steps. In contrast, the
direct bromination of 3-chlorothiophene with NBS has been
reported to form 2-bromo-3-chlorothiophene.[22] Likewise, the
sequential silylation and iodination of 3-methoxythiophene formed
4
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2,4-functionalized product 27, whereas direct iodination of the
unfunctionalized arene is known to form the 2,3 functionalized
product.[23] Heteroarylsilanes also undergo coupling reactions to
form arylated products. The silylation of 3-methoxythiophene at
the 5-position followed by Hiyama cross-coupling in the presence
of a palladium catalyst furnished 5-arylated product 28 in 58%
yield over 2 steps. Previous literature reported that the direct
arylation of 3-methoxythiophene, when catalyzed by rhodium or
palladium complexes, leads to arylation with high selectivity for
the 2-position,[24] although direct arylation of 3-methoxythiophene
at the 5- position does occur with diaryliodonium salts in the
presence of a Cu/Fe catalyst.[25] The 5-arylated product 29 formed
in 67% yield over two steps by the sequential silylation and cross-
coupling of ethyl 3-furancaryboxylate. In contrast, ethyl 3-
furancarboxylate is known to undergo direct arylation at the 2-
position in the presence of Pd(PPh3)4 as catalyst and undergoes
arylation at the 5-position with a modest 3 to 1 selectivity in the
presence of Pd/C.[26]
octylthiophene was formed by this process in 61% yield by NMR
spectroscopy and 37% isolated yield. These results demonstrate
that the silylations of heteroarenes with high sterically derived
regioselectivity, followed by functionalizations of the resulting
heteroarylsilanes, generate products that are distinct from those
accessible from the direct functionalization of the same
heteroarenes.
The silyl-azoles presented in Scheme 4 are more electron-
deficient than the silyl-thiophenes and silyl-furans in Scheme 5.
To determine whether silyl-azoles are nucleophilic enough to
undergo transformations that are similar to those of other silyl-
arenes and heteroarenes, we conducted
a
series of
derivatizations of silyl pyrazole 31 (Scheme 6). The reaction of 31
with NCS in the presence of AgF formed chloropyrazole 32 in 52%
yield. Similarly, the reaction of 31 with NBS formed
bromopyrazole 33 in 81% yield. Silyl-pyrazole 31 also coupled
with 3,5-(MeO)2-phenyl triflate to form biaryl 34 in 70% yield when
catalyzed by Pd2dba3·CHCl3 and BINAP. The identification of that
catalyst system is discussed in greater detail below. In addition,
31 coupled with (phen)CuCF3 under an atmosphere of oxygen to
form 1-Ts-3-Me-4-CF3-pyrazole (35) in 50% yield. These results
demonstrate that the silylation of azoles, followed by the
functionalization of the product, also can lead to products
containing a diverse array of functional groups.
Scheme 5. Regio-Divergent Functionalization of Heteroarenesa
Scheme 6. Transformations of Silyl-Pyrazolea
aSee SI for detailed procedures.
aSee SI for detailed procedures.
Suzuki couplings are widely used, in part, because the aryl
boronic acid and ester reagents are stable to air and moisture and
can be stored. However, as discussed, the boronic acids or esters
of azoles are often unstable. Therefore, coupling of the more
stable silyl derivatives of five-membered heteroarenes would be
valuable. We found that the silyl-thiophenes and silyl-furans that
result from the silylation of C–H bonds couple with aryl iodides in
the presence of AgF and catalytic amounts of Pd(PtBu3)2.
However, under similar conditions, only 10% of the product from
the reaction of the silyl thiazole 2-silyl-4-thiazolecarboxylate
methyl ester formed from coupling the representative partner m-
Finally, the silylation of 3-methylthiophene, followed by
coupling (phen)CuCF3 under an atmosphere of oxygen, formed
the product from trifluoromethylation of the 5-position of the
thiophene. In contrast, the direct addition of trifluoromethyl radical
is known to occur at the 2-position of 3-methylthiophene.[27] Due
to the volatility of 2-trifluoromethyl-4-methylthiophene, this
product, was characterized by the 19F NMR of the crude reaction
mixture. However, to form an isolable analog, the silylation of 3-
octylthiophene and coupling of the silyl thiophene with a source
of trifluoromethyl group was studied, and 2-trifluoromethyl-4-
5
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Cl-iodobenzene (Scheme 7). After conducting reactions with a
series of fluoride additives and phosphine ligands, we found that
a high yield of biaryl product (85%) was obtained from reactions
with CsF as activator and the combination of Pd2dba3·CHCl3 and
BINAP as catalyst. The 2-silyl-4-thiazolecarboxylate methyl ester
also coupled with heteroaryl bromides catalyzed by the same
system to form biaryls 37 and 38 in 76% and 50% yield. Although
bithiazole 39 formed in a modest 22% yield from the same
coupling of the silyl thiazole with 2-bromothiazole, this reaction
has not been accomplished previously by Suzuki coupling of the
analogous boronate, presumably due to the instability of this
boronate. As noted in the previous paragraph, these conditions
were also suitable for the coupling of the silyl-pyrazole 31 to form
3-aryl pyrazole 34. Thus, the combination of CsF activator and
BINAP-ligated palladium is an effective system to catalyze the
coupling of silylazoles with aryl halides under mild conditions.
products 7c and 7d, respectively. This reaction occurred in
concert with the formation of silylated products 7a and 7b. After
15 min at 65 °C, the amounts of deuterated products 7c and 7d
were greater than the amounts of silylated products 7a and 7b by
factors of about 2:1 and 6:1 for the catalysts containing ligands
Me2phen and L4, respectively. This incorporation of deuterium
into the heteroarene reactant indicates that cleavage of the C–H
bond is reversible.
The ratio of deuterated products was distinct from the ratio
of silylated products. The reaction catalyzed by the complex of
Me2phen formed deuterated products 7c and 7d in a ratio of 1.5:1
but formed the silylated products 7a and 7b in a higher ratio of
2.9:1 (Scheme 8). The reaction catalyzed by a complex of L4
formed the deuterated products 7c and 7d in a ratio of only 1.1:1
but formed the silylated products 7a and 7b in a high ratio of 14:1.
Thus, the cleavage of C–H bonds by the catalyst that contains L4
is less regioselective than that of the catalyst that contains
Me2phen, but the formation of silylated products by the catalyst
that contains L4 occurs with much greater regioselectivity than
that of the catalyst that contains Me2phen. These results
demonstrate that the regioselectivity of these two catalysts for the
silylation of C–H bonds does not reflect the propensity of the
catalysts to cleave C–H bonds. Rather, the selectivity of the
silylation reaction is controlled by the relative rates of formation of
the carbon-silicon bond from 2- or 5-heteroaryliridium
intermediates that are formed reversibly. These experimental
results resemble the computations reported by Sakaki for the
selectivity of the borylations of β over α C–H bonds in THF, as
well as the experiments and computations our group reported
previously on the origins of selectivity of Rh-catalyzed borylations
and silylations of primary over secondary alkyl C–H bonds.[28]
Scheme 7. Hiyama Coupling of Silyl-Azolesa
Scheme 8. Reactions of Deuterated Silane with Excess Arenea
Conclusion
In summary, we have developed a method for the silylation
of heteroaromatic compounds with high sterically derived
regioselectivity. In many cases, these high selectivities are
achieved with a new pyridyl-imidazoline ligand L4. The selectivity
of this silylation to form functionalized products from reaction at
the least sterically hindered position of five-membered
heteroarenes is much higher than that of previously reported
borylations of these heteroarenes, and the products formed are
much more stable than the analogous boronates. Moreover,
functionalizations of the heteroarylsilanes form products with
substitution patterns that are orthogonal to those that have been
reported by traditional methods and other catalytic processes.
aSee SI for detailed procedures. b3% Pd/L. cDetermined by 1H NMR
spectroscopy with dibromomethane internal standard.
4. Origin of Regioselectivity
To determine the elementary steps controlling the high
selectivity for the silylation of unhindered C–H bonds of
heteroarenes catalyzed by complexes of L4, we conducted
studies on the reactions of deuterated silane with 3-
chlorothiophene (7). The reactions of an excess of 7 with
deuterated silane catalyzed by iridium and Me2phen or L4
exchanged deuterium between the silane Si–D bond and the 2-
positions and 5-positions of the heteroarene to form deuterated
6
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10.1002/anie.201916015
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RESEARCH ARTICLE
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We gratefully acknowledge financial support from the NIH
(R35GM130387). We thank the College of Chemistry's NMR
facility for resources provided and the staff for their assistance.
Instruments in CoC-NMR are supported in part by the NIH
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Keywords: Silylation • Heteroarenes • C-H Functionalization •
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7
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10.1002/anie.201916015
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RESEARCH ARTICLE
Entry for the Table of Contents
The silylation of five-membered heteroarenes occurs with high sterically derived regioselectivity when catalyzed by the combination
of [Ir(cod)(OMe)]2 and a novel pyridyl-imidazoline ligand. The silylation reactions with this catalyst produce high yields of
heteroarylsilanes under conditions in which the borylation of C–H bonds with previously reported catalysts formed mixtures of
products or products that are unstable.
Institute and/or researcher Twitter usernames: @HartwigGroup
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