Iridium-catalyzed arene ortho -silylation by formal hydroxyl-directed C-H activation

Article abstract of DOI:10.1021/ja1086547

A strategy for the ortho-silylation of aryl ketone, benzaldehyde, and benzyl alcohol derivatives has been developed in which a hydroxyl group formally serves as the directing element for Ir-catalyzed arene C-H bond activation. One-pot generation of a (hyd

Full text of DOI:10.1021/ja1086547

Published on Web 11/15/2010
Iridium-Catalyzed Arene Ortho-Silylation by Formal Hydroxyl-Directed C-H
Activation
Eric M. Simmons and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801, United States
Received September 25, 2010; E-mail: jhartwig@illinois.edu
lack of scope, and limited reactivity of the tetraorganosilane product.
Abstract: A strategy for the ortho-silylation of aryl ketone,
benzaldehyde, and benzyl alcohol derivatives has been devel-
oped in which a hydroxyl group formally serves as the directing
element for Ir-catalyzed arene C-H bond activation. One-pot
Second, we reported the silyl-directed borylation of aromatic
alcohols.6 In this case, the reactions did not occur with benzylic
alcohols and led to organoboron, not organosilicon, products.
With these results in mind, we envisioned that a hydroxyl group
generation of a (hydrido)silyl ether from the carbonyl compound
might direct7 the ortho-silylation of arenes by initial formation of
or alcohol is followed by dehydrogenative cyclization at 80-100
a (hydrido)silyl ether (3), followed by a catalytic intramolecular
°C in the presence of norbornene as a hydrogen acceptor and
the combination of 1 mol % [Ir(cod)OMe]2 and 1,10-phenanthro-
line as a catalyst to form benzoxasiloles. The synthetic utility of
the benzoxasilole products is demonstrated by conversion to
dehydrogenative cyclization (Figure 1, bottom). Because the C-H
bond functionalization step is intramolecular, the formation of bis-
silylated products is avoided. Furthermore, the presence of the Si-O
bond in the resulting benzoxasilole (4)8,9 would allow the product
phenol or biaryl derivatives by Tamao-Fleming oxidation or
to undergo synthetically useful processes, such as Tamao-Fleming
Hiyama cross-coupling. Both of these transformations of the C-H
oxidation10 and Hiyama cross-coupling.11
silylation products exploit the Si-O bond in the system and
proceed by activation of the silyl moiety with hydroxide, rather
than fluoride.
The site-selective functionalization of traditionally inert carbon-
hydrogen bonds with transition-metal catalysts is creating new
strategies for the construction of functionalized organic molecules.1,2
Among these strategies, the silylation of C-H bonds is particularly
attractive because silanes are usually inexpensive, nontoxic, and
environmentally benign, and appropriately substituted organosilanes
undergo a variety of transformations to form useful derivatives.
Since seminal reports on intermolecular dehydrogenative arene
silylation first appeared in the 1980s,3 significant advances have
been documented, and a variety of directing groups have been
identified in recent years that lead to the regioselective ortho-
silylation of arenes with hydrosilane coupling partners.4
Despite the progress that has been made, current ortho-silylation
processes are typically limited in three ways: (1) Specialized
directing groups are often needed that are not commonly found in
the final desired product and are not easily installed and removed;
Figure 1. (Hydrido)silyl-directed arene C-H bond activation.
(2) mixtures of mono- and bis-silylated products are often observed
from reactions of substrates containing two ortho C-H bonds; and
(3) triorganosilanes are often required for the catalytic process, and
these reagents generate tetraorganosilane products, which do not
undergo coupling and oxidation processes. We report the develop-
ment of a regioselective ortho-silylation of benzyl alcohols to form
silylated products. The regioselectivity of the silylation process is
controlled by a simple hydroxyl group, and the products possess a
Si-O bond. Therefore, this reaction can be used as a mild, catalytic
method to access arylsilane reagents that undergo cross-coupling
and oxidation processes to form C-C and C-O bonds.
The new ortho-silylation of arenes described here originates from
the combination of two prior observations from our laboratory
(Figure 1, top). First, we reported platinum-catalyzed intramolecular
silylation of ꢀ-phenethyl dimethylsilane at 200 °C.5 Although this
reaction was the first intramolecular arene silylation, the synthetic
utility of this reaction was limited by the harsh reaction conditions,
We initiated our studies by examining conditions to generate
the requisite (hydrido)silyl ethers. Phenol derivatives were reported
previously to form the corresponding diethyl(hydrido)silyl ethers
by treatment with Et2SiH2 and catalytic [Ir(cod)Cl]2 (0.5 mol %)
in benzene.6a,12 We found that [Ir(cod)X]2 (X ) Cl, OMe) also
catalyzes the hydrosilylation of various carbonyl compounds (5)
with Et2SiH2 (1.2 equiv) in THF at room temperature and that these
reactions occur with a catalyst loading of just 0.05 mol % (eq 1).13
These conditions provide the corresponding diethyl(hydrido)silyl
ethers (6) from a wide range of ketones, aldehydes, and alcohols
without the need for purification of the silyl ether product.
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C O M M U N I C A T I O N S
Table 1. Benzoxasilole Products Derived from 2° and 3° Silyl Ethersa
Having established this route to (hydrido)silyl ethers, we sought
to identify conditions for intramolecular dehydrogenative silylation.
We began by testing reactions with silyl ether 6a (eq 2) catalyzed
by the combination of [Ir(cod)OMe]2 and 4,4′-di-tert-butylbipyridine
(dtbpy), which catalyzes the borylation of arenes.14 After heating
a solution of 6a (0.25 mmol) and 1 mol % of this catalyst in THF
for 16 h at 120 °C, 73% conversion of 6a and 31% yield of the
corresponding cyclized product (7a) were observed by GC.
However, reactions catalyzed by [Ir(cod)OMe]2 and 1,10-phenan-
throline (phen) under otherwise identical conditions occurred with
higher conversion (88%) and substantially higher yield (66%) of
7a. Although dehydrogenative cyclization proceeds in the absence
of any added H2 scavenger, reactions with 1.2 equiv of added
norborene and phen as the ligand occurred to full conversion after
16 h at 120 °C to give 87% yield of 7a.15 Moreover, the same
reaction at the lower temperature of 80 °C for 16 h gave a
comparable 90% yield of 7a. Faster rates were also observed when
norbornene was added to reactions conducted with dtbpy as the
ligand, but the yields for these reactions were lower than those for
reactions conducted with phen as the ligand. Under our optimized
conditions, benzoxasilole (7a) was obtained in 73% overall isolated
yield from acetophenone (1.0 mmol scale) by hydrosilylation and
intramolecular dehydrogenative arene silylation, followed by
standard silica gel chromatography.16
a Isolated yields for reactions conducted on
a 1.0 mmol scale
following purification by silica gel chromatography. b Isolated yield for
reaction conducted on a 5.0 mmol scale (using 0.5 mol % [Ir]/phen at
100 °C). c Cyclization conducted at 50 °C. d Cyclization conducted at
100 °C. e Product isolated by bulb-to-bulb distillation.
Table 2. Benzoxasilole Products Derived from 1° Silyl Ethersa
The scope of the directed silylation of arenes is shown in Tables
1 and 2. As shown in Table 1, a range of substituted benzoxasilole
products were obtained in good yields by cyclization of secondary
(2°) and tertiary (3°) (hydrido)silyl ethers, which were prepared in
situ from the corresponding alcohol or ketone precursors. Monoalkyl
(7a-d), dialkyl (7e), and aryl (7f) substituents were all tolerated
at the R-position of the silyl ether. Formation of a five-membered
ring was much faster than formation of a six-membered ring, as
exemplified by benzyl-substituted benzoxasilole 7d. In addition to
simple benzoxasiloles, tricyclic (7g) and heteroaromatic (7h)
products were accessible by this procedure. Halogen substituents
(7i-j) were tolerated under the reaction conditions, as was a
boronate ester group (7k). In addition, substrates bearing silyl ether,
ester, and dialkylamino groups underwent cyclization in good yield
(7m-o). However, functional groups that are potentially sensitive
to silane-mediated reduction, such as a nitro group, were incompat-
ible with the reaction conditions. Although (hydrido)silyl ethers
containing a terminal double bond did not undergo high-yielding
cyclization, presumably due to competitive oligomerization from
intermolecular reaction of the silane with the alkene, substrates
containing cis or trans 1,2-disubstituted alkenes were cyclized in
good yield (7p-q), with >95% retention of olefin geometry (as
a Isolated yields for reactions conducted on a 1.0 mmol scale following
purification by bulb-to-bulb distillation. b Cyclization conducted at 120 °C.
c Obtained as an inseparable mixture of constitutional isomers in a 1.0:0.79
ratio, as determined by 1H NMR.
products (7a, 7c, 7i, 7o) in yields similar to those of reactions
conducted on a 1 mmol scale.
1
determined by GC and H NMR analysis). The selectivity from
reactions of substrates that can undergo cyclization to form two
constitutional isomers (7l-q) was consistently greater than 20:1,
favoring reaction at the less sterically hindered C-H bond. This
selectivity mirrors the high selectivity from sterically controlled
C-H borylation catalyzed by Ir-bipyridine complexes.14 Finally,
we found that the silylation reaction could be conducted with 5
mmol of substrate to provide the corresponding benzoxasilole
Cyclization of primary (hydrido)silyl ethers derived from ben-
zaldehyde and benzyl alcohol precursors also occurred, and these
reactions are summarized in Table 2.17 Reactions of these substrates
required a slightly higher temperature of 100 °C to occur to
completion, but full conversion was still observed with just 1 mol
% catalyst. Benzoxasiloles possessing ortho alkyl groups (8a-b)
or small halogens (8c-d) were accessible by the cyclization of
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C O M M U N I C A T I O N S
primary (hydrido)silyl ethers. These results contrast with those from
reactions of ortho-substituted secondary (hydrido)silyl ethers, which
did not provide the corresponding benzoxasiloles in high yield. Like
reactions of ortho-substituted secondary (hydrido)silyl ethers,
reactions of primary (hydrido)silyl ethers containing ortho-bromo
and ortho-iodo substituents were low-yielding, likely due the larger
size of these substituents. However, a para-iodo substituent was
well tolerated by the silylation process (8e).
base-mediated hydrolysis of the benzoxasilole at the Si-O bond might
generate an aryl silanolate species capable of undergoing transmeta-
lation.23 After evaluating a series of reaction conditions, we found that
the combination of Pd(OAc)2 and 1,2-bis(dicyclohexylphosphino)et-
hane (dcpe) in dioxane at 65 °C, in the presence of 5 equiv of 2 M aq
NaOH, mediated the coupling of a series of aryl iodides with
benzoxasiloles (7) derived from secondary alcohols. As shown in Table
4, a range of biaryl products were obtained in good yield from cross-
coupling with electron-neutral (10a), electron-rich (10c, 10e), and
electron-deficient (10d, 10f) aryl iodides, as well as heteroaryl coupling
partners (10b). The conditions shown in Table 4 were also effective
for the cross-coupling of benzoxasiloles with aryl bromides and
chlorides. The biaryl products 10a, 10e, and 10f were isolated from
reactions of these aryl halides in moderate to good yields. Finally, a
one-pot sequence of hydrosilylation, ortho-silylation, and Hiyama
coupling of acetophenone on a 1.0 mmol scale provided 10a in 63%
overall isolated yield.22
To probe further the origin of the high regioselectivity observed
for the cyclization of meta-substituted silyl ethers, a series of primary
(hydrido)silyl ethers bearing meta substituents with varying steric and
electronic properties were prepared and allowed to cyclize to the
corresponding benzoxasiloles (8f-j). Only the reaction with the
substrate containing the less sterically biased 3-fluoro substituent
yielded a mixture (1.0:0.79) of constitutional isomers (8j). All others
generated a >20:1 ratio of product from silylation at the less hindered
position to product from silylation at the more hindered position. This
result is consistent with the hypothesis that the regioselectivity of this
cyclization is governed by steric, rather than electronic, factors.
To develop the synthetic utility of the benzoxasilole products,
we sought to identify conditions to transform the Ar-Si linkage
into a C-O or C-C bond. A Tamao-Fleming oxidation would
correspond to a net ortho-oxygenation of the initial benzylic
alcohol.8m,10,18,19 As illustrated in Table 3, this transformation
proceeded upon treatment of benzoxasiloles (7 or 8) with H2O2
and KHCO3 in THF/MeOH at room temperature. The fact that
oxidation of these substrates occurs without the typical need for
fluoride additives20 both increases the operational simplicity of this
procedure and also allows for the preparation of silyl ether
derivatives such as 9e without any detectible desilylation of the
TBS moiety. Furthermore, we were able to use these conditions to
prepare oxygenated aryl iodide 9g, which would be difficult to
obtain by classical DoM methodology due to competitive metal-
halogen exchange.19,21 These transformations can all be conducted
in one pot. A sequence of hydrosilylation, ortho-silylation, and
oxidation in the same flask beginning with acetophenone on a 1.0
mmol scale provided 9a in 57% overall isolated yield.22
Table 4. Hiyama Coupling of Benzoxasilolesa
a Conditions: 7 (1 equiv), aryl iodide (1.2 equiv), Pd(OAc)2 (4 mol
%), dcpe (4.5 mol %), 2 M aq NaOH (5 equiv), dioxane, 65 °C; isolated
yields for reactions conducted on
a 0.25 mmol scale following
purification by silica gel chromatography. b Isolated yield for reaction
conducted using aryl bromide (1.2 equiv). c Isolated yield for reaction
conducted using aryl chloride (1.2 equiv).
Table 3. Tamao-Fleming Oxidation of Benzoxasilolesa
During the course of our studies to optimize the Hiyama coupling
of benzoxasiloles, we discovered that these species are unreactive
in the presence of weak bases, such as phosphate or carbonate.
Because such bases are commonly used to activate boronic acid
derivatives toward transmetalation, we investigated the possibility
of conducting an orthogonal Suzuki-Miyaura coupling with a
halogen-containing benzoxasilole. As shown in Scheme 1, coupling
of bromo-benzoxasilole 7i with 3,5-dimethylphenylboronic acid
promoted by K2CO3 proceeded smoothly to generate biaryl ben-
zoxasilole 11 in 89% yield. Subsequent Hiyama coupling of 11
with 4-iodoanisole promoted by NaOH provided triaryl benzyl
alcohol 12 in 79% yield. This sequence could also be run as a one-
pot procedure, giving 12 in 65% overall yield from 7i.22 These
Scheme 1. Orthogonal Cross-Coupling of Benzoxasilole 7ia
a Conditions: (a) 7 or 8 (1 equiv), KHCO3 (2.0 equiv), 30% H2O2
(8.0 equiv), 1:1 THF/MeOH, rt; (b) Ac2O (3.0 equiv), 2:1 CH2Cl2/Et3N,
rt; (c) TBSCl (2.5 equiv), imidazole (3.0 equiv), DMF, rt; (d) BnBr
(1.25 equiv), K2CO3 (1.5 equiv), TBAI (0.1 equiv), acetone, 65 °C;
isolated yields (over 2 steps) for reactions conducted on a 0.50 mmol
scale following purification by silica gel chromatography. b Oxidation
conducted at 40 °C.
In addition to developing conditions for the Tamao-Fleming
oxidation of the benzoxasiloles, we developed conditions for Hiyama-
type coupling of the benzoxasiloles with aryl halides. Based on the
recent success of Denmark and co-workers in conducting Hiyama
couplings with organosilanolate nucleophiles,11a we hypothesized that
a Conditions: (a) 7i (1 equiv), 3,5-dimethylphenylboronic acid (1.2 equiv),
K2CO3 (2.5 equiv), Pd(PCy3)2Cl2 (2 mol %), THF/H2O, 65 °C; (b)
4-iodoanisole (1.2 equiv), Pd(OAc)2 (4 mol %), dcpe (4.5 mol %), 2 M aq
NaOH (5 equiv), dioxane, 65 °C.
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silylation to build molecular complexity.
Although the mechanistic details of the present silylation have
yet to be elucidated, some insight into the C-H bond activation
step may be gained from the regioselectivity observed for the
silylation of 4-chlorobenzophenone, which produced a mixture of
constitutional isomers 13a and 13b in a 71:29 ratio (eq 3). Although
the regioselectivity is only modest, the slight preference for
silylation of the more electron-deficient C-H bond is consistent
with C-H bond cleavage proceeding by an oxidative addition
mechanism, rather than an electrophilic metalation pathway.
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In summary, we report a new strategy for arene ortho-silylation
in which a hydroxyl group serves as the directing element for Ir-
catalyzed C-H bond activation via dehydrogenative cyclization of
in situ generated diethyl(hydrido)silyl ethers. This transformation
proceeds under relatively mild conditions (80-100 °C) with low
catalyst loadings (1 mol %), and a range of functional groups were
found to be compatible with the reaction conditions. The ability to
conduct C-H bond functionalization with a substrate containing a
Si-O bond is unusual and makes possible the synthetically useful
conversions of the benzoxasilole products to phenol and biaryl
derivatives by Tamao-Fleming oxidation and Hiyama cross-
coupling. Both of these transformations of the silylated products
can be conducted as a part of a one-pot ortho-silylation/function-
alization procedure, without the need for isolation of the intermedi-
ate benzoxasilole. Further studies to expand the substrate scope
and to gain insight into the C-H activation and C-Si bond-forming
steps of this transformation are currently in progress.
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Acknowledgment. We thank the NSF (CHE-0910641) to J.F.H.
and NIH (GM087901) to E.M.S. for funding of this work and
Johnson Matthey for a gift of [Ir(cod)OMe]2 and Pd(OAc)2. E.M.S.
thanks Dan Robbins and Carl Liskey for insightful discussions.
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Supporting Information Available: Complete experimental details
and characterization of new products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) The accelerating effect of norbornene on Ir-catalyzed C-H activation has
been observed previously; see: (a) Lu, B.; Falck, J. R. Angew. Chem., Int.
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1701–1705.
(16) Although purification of the diethyl(hydrido)silyl ethers was found to be
unnecessary, removal of the volatiles (by placing the reaction mixture under
vacuum) was necessary to prevent poisoning of the second charge of
[Ir(cod)OMe]2 by residual Et2SiH2, in line with previous observations (see
ref 6a).
(17) The benzoxasilole products derived from primary silyl ethers proved
sensitive to silica gel chromatography but were readily purified by bulb-
to-bulb distillation of the concentrated reaction mixture.
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Reference 19. (b) Tamao, K.; Ishida, N. J. Organomet. Chem. 1984, 269,
c37–c39.
(4) For examples using hydrosilanes, see: (a) Kakiuchi, F.; Igi, K.; Matsumoto,
M.; Chatani, N.; Murai, S. Chem. Lett. 2001, 422–423. (b) Kakiuchi, F.;
Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani, N.; Murai, S. Chem.
Lett. 2002, 396–397. (c) Kakiuchi, F.; Matsumoto, M.; Tsuchiya, K.;
Igi, K.; Hayamizu, T.; Chatani, N.; Murai, S. J. Organomet. Chem. 2003,
686, 134–144. (d) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131,
7502–7503. For examples using other silane species, see: (e) Kakiuchi,
F.; Matsumoto, M.; Sonoda, M.; Fukuyama, T.; Chatani, N.; Murai, S.;
(21) Snieckus, V. Chem. ReV. 1990, 90, 879–933.
(22) See the Supporting Information for details.
(23) For the NaOH-promoted cross-coupling of aryl- and alkenyl(dichloro)si-
lanes, in which in situ generated organosilanolates are likely intermediates,
see: Hagiwara, E.; Gouda, K.-i.; Hatanaka, Y.; Hiyama, T. Tetrahedron
Lett. 1997, 38, 439–442.
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