PyDipSi: A general and easily modifiable/traceless Si-tethered directing group for C-H acyloxylation of arenes

Article abstract of DOI:10.1021/ja1033167

A new general and easily installable silicon-tethered pyridyl-containing directing group (PyDipSi) that allows for highly efficient and regioselective Pd-catalyzed ortho C-H acyloxylation of arenes has been developed. It has also been demonstrated that this directing group can efficiently be removed as well as converted into a variety of other valuable functional groups. In addition, the installation of the PyDipSi directing group along with pivaloxylation and quantitative conversion of the PyDipSi group into a halogen functionality represents a formal three-step ortho oxygenation of haloarenes.

Full text of DOI:10.1021/ja1033167

Published on Web 05/28/2010
PyDipSi: A General and Easily Modifiable/Traceless Si-Tethered Directing
Group for C-H Acyloxylation of Arenes
Natalia Chernyak, Alexander S. Dudnik, Chunhui Huang, and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received April 19, 2010; E-mail: vlad@uic.edu
Palladium-catalyzed, ligand-directed C-H functionalization has
emerged as a powerful tool for the direct conversion of arenes into
a variety of valuable products.1 Among these transformations, Pd-
catalyzed directed acetoxylation reactions of aromatic C-H bonds2,3
are particularly attractive because they allow the direct formation
of oxygenated arenes.4 A variety of directing groups, such as
pyridine,3a,c,g pyrimidine,3e,j pyrazole,3e oxazoline,3d,e amide,3f,k
and oxime ether,3d have been shown to be efficient in these
Figure 1. Substrates for optimization of the silicon tether.
reactions. However, despite the achieved high yields and selectivi-
ties, the acyloxylation reactions somewhat lack generality, as the
majority of the directing groups, which are necessary for the
toward PhI(OAc)2 at 80 °C, producing the desired product 2a
in 15% yield (entry 3). Increasing the temperature to 100 °C
selective transformation, often cannot easily be removed from the
products, thus limiting these methodologies to particular types of
substrates (eq 1). Herein we report the use of the pyridyldiisopro-
pylsilyl (PyDipSi) group as a new silicon-tethered directing group
that allows for efficient acetoxylation/pivaloxylation of aromatic
C-H bonds. Most importantly, this directing group can efficiently
be removed or converted into a variety of other functional groups
(eq 2).
led to a slight improvement in the reaction outcome (entry 4).
Addition of a stoichiometric amount of Cu(OAc)2 gave only
traces of product (entry 5). Surprisingly, employment of 1 equiv
of AgOAc7 resulted in a dramatic improvement in the reaction,
affording the desired 2a in 70% yield. Furthermore, performing
the reaction at slightly higher temperature (100 °C) resulted in
a better yield of 2a (80%, entry 7). Finally, switching the solvent
to dichloroethane (DCE) provided the highest yield of the product
(85%) at lower temperature (80 °C) (entry 8).
Table 1. Optimization of the Ortho Acetoxylation Reaction
Conditions
Our approach to the design of the removable directing group
was based on the employment of a temporary silicon tether to
connect a good metal-coordinating group for C-H activation
with an aromatic substrate of interest. We thought that employ-
ment of a silicon-tethered directing group5,6 would bring a certain
advantage, since it is easily removable from the products of C-H
functionalization. We chose pyridine as a platform for our new
group design because it is known to be superior in coordinating
palladium in directed C-H activation processes.1j To this end,
we aimed at establishing a suitable silicon tether for the pyridine
group. Accordingly, substrate A containing a pyridyldimethylsilyl
directing group (Figure 1), which was previously developed by
Yoshida5 for the highly regio- and stereoselective Pd-catalyzed
Heck arylation of vinylsilanes,5b was tested first. However, the
reaction with PhI(OAc)2 in the presence of 10 mol % Pd(OAc)2
in PrCN at 80 °C3a resulted in total decomposition of the starting
arylsilane A with no formation of the desired product (Table 1,
entry 1). To further optimize the silicon tether, the silacyclo-
pentane (B) and diisopropylsilyl (1a) derivatives were synthe-
sized (Figure 1). Similarly to A, compound B appeared to be
unstable as well (Table 1, entry 2). However, we were pleased
to find that the diisopropylsilyl derivative 1a was more stable
entry
substrate
additive (equiv)
solvent
T (°C)
yield (%)a
b
1
2
3
4
5
6
7
8
A
B
none
none
none
none
Cu(OAc)2 (1)
AgOAc (1)
AgOAc (1)
AgOAc (1)
PrCN
PrCN
PrCN
PrCN
PrCN
PrCN
PrCN
DCE
80
80
80
100
100
80
100
80
-
b
-
1a
1a
1a
1a
1a
1a
15 (2a)b
30 (2a)b
trace (2a)
70 (2a)
80 (2a)
85 (2a)
a NMR yield. b Decomposition of the starting arylsilane was
observed.
It should be mentioned that the synthesis of arylsilanes containing
the PyDipSi directing group is straightforward (Scheme 1). First,
pyridyldiisopropylsilane is obtained in excellent yield from com-
mercially available 2-bromopyridine and diisopropylsilyl chloride.
Next, the hydride-substitution reaction in pyridyldiisopropylsilane
with in situ-generated aryllithium reagents affords arylsilanes 1 in
high yields (Scheme 1).
With the optimized conditions in hand, the generality of the
Pd-catalyzed acyloxylation reaction of PyDipSi-containing arenes
1 was examined (Table 2). To our delight, it was found that
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10.1021/ja1033167  2010 American Chemical Society

C O M M U N I C A T I O N S
synthetically valuable pivaloxy group9 were synthesized in good
to excellent yields. A variety of functional groups, including
OMe (entries 2c-e), F (entries 2q and 2t), Cl (entries 2p, 2r,
and 2u), Br (entries 2o and 2s), pinacol-protected aldehyde (entry
2v), CO2Et (entry 2w), and CON(i-Pr)2 (entry 2x), were perfectly
tolerated under these reaction conditions. Notably, substrates
containing meta substituents displayed excellent regioselectivity
in both the acetoxylation and pivaloxylation reactions, producing
the corresponding oxygenated products as single regioisomers
in high yields (2c, 2f-h, 2n, 2o, 2t, 2u). Remarkable site
selectivity was also observed in acetoxylation and pivaloxylation
of 2-naphthyl derivatives, yielding the desired compounds as
sole isomers (entries 2l and 2m).
Scheme 1. Synthesis and Installation of the PyDipSi Directing
Group
Our initial mechanistic studies indicated that electron-rich arenes
were acyloxylated more rapidly than electron-deficient ones.10,11
In addition, the substantial value of kH/kD (6.7) was observed in
intramolecular kinetic isotope effect (KIE) studies of the pivaloxy-
lation reaction of 1a-d1 (Scheme 2).12 It is believed that the present
Pd-catalyzed acyloxylation reaction follows the C-H activation
pathway.3b,e,h,i,13
Table 2. Pd-Catalyzed Ortho Acyloxylation of Arylsilanesa b
,
Scheme 2. Intramolecular Kinetic Isotope Effect Studies
Naturally, after the development of the efficient directed C-H
acyloxylation of arylsilanes, we explored further transformations
of the PyDipSi group of the product 2g (Scheme 3). First, it
was found that the reaction of 2g with AgF14 in methanol
resulted in efficient deprotection of the directing group, affording
tolylpivalate (3) in 92% yield. Moreover, treatment of 2g with
AgF in tetrahydrofuran (THF)/D2O produced the deuterated
tolylpivalate 3-d1 in 95% yield. Remarkably, use of a combina-
tion of AgF and N-iodosuccinimide (NIS) resulted in quantitative
conversion of the PyDipSi group into an iodide functionality.
The latter transformation, taken together with the installation
and pivaloxylation steps, represents a formal three-step ortho
oxygenation of 3-iodotoluene.15 Furthermore, 2g was converted
into the synthetically valuable arylboronate 516 in 94% yield
via
a one-pot sequence involving borodesilylation with
Scheme 3. Further Transformations of the PyDipSi Group
a Isolated yields. b See the Supporting Information for details.
this transformation is highly efficient for the exclusive monoa-
cyloxylation of a wide range of substrates. Thus, arylsilanes
2a-x possessing the acetoxy group8 and the even more
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C O M M U N I C A T I O N S
BCl3followed by protection with pinacol.17 In addition, borode-
silylation of 2g followed by oxidation in the presence of H2O2/
NaOH produced substituted catechol 6 in excellent yield. Finally,
it was found that the acetoxy derivative 2a underwent an efficient
Hiyama-Denmark cross-coupling18 with phenyl iodide and
subsequent hydrolysis of the acetoxy group, providing 2-phe-
nylphenol (7) in 93% yield (Scheme 3).
In summary, we have shown that the PyDipSi group can serve
as new, general directing group for the Pd-catalyzed acyloxy-
lation of arenes, providing access to a variety of acetoxylated
and pivaloxylated aromatic compounds in good yields. Most
importantly, it was shown that this newly designed directing
group could efficiently be cleaved or converted into other
valuable functional groups such as iodide and boronate. Finally,
borodesilylation of this directing group under oxidative condi-
tions allowed for the preparation of a substituted catechol,
whereas Hiyama-Denmark cross-coupling provides direct access
to o-hydroxybiphenyl.
(4) For a recent review of transition-metal-catalyzed syntheses of hydroxylated
arenes, see: Alonso, D. A.; Na´jera, C.; Pastor, I. M.; Yus, M. Chem.sEur.
J. 2010, 16, 5274.
(5) For employment of the pyridyldimethylsilyl directing group in Heck
arylations, see: (a) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Nokami,
T.; Yoshida, J.-I. J. Am. Chem. Soc. 2000, 122, 12013. (b) Itami, K.;
Nokami, T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 5600. (c) Itami,
K.; Ushiogi, Y.; Nokami, T.; Ohashi, Y.; Yoshida, J.-I. Org. Lett. 2004, 6,
3695.
(6) For employment of the dimethylhydrosilyl directing group in Ir-catalyzed
C-H borylations, see: (a) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F.
J. Am. Chem. Soc. 2010, 132, 4068. (b) Boebel, T. A.; Hartwig, J. F. J. Am.
Chem. Soc. 2008, 130, 7534.
(7) The role of AgOAc is currently unclear. We believe it helps maintain an
effective concetration of reactive Pd(OAc)2 species.
(8) For a recent example of an acetate cross-coupling reaction, see: Guan, B.-
T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130,
14468.
(9) For representative examples of pivalate cross-coupling reactions, see: (a)
Li, B.-J.; Li, Y.-Z.; Lu, X.-Y.; Liu, J.; Guan, B.-T.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2008, 47, 10124. (b) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am.
Chem. Soc. 2008, 130, 14422. (c) Shimasaki, T.; Tobisu, M.; Chatani, N.
Angew. Chem., Int. Ed. 2010, 49, 2929. For a review, see: (d) Goossen,
L. J.; Goossen, K.; Stanciu, C. Angew. Chem., Int. Ed. 2009, 48, 3569. For
a recent example of pivalate-directed C-H arylation, see: (e) Xiao, B.;
Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc.
2009, 132, 468.
Acknowledgment. This work is dedicated to the memory of
Prof. Alexey Andreev. We thank the National Institutes of Health
(Grant GM-64444) for financial support of this work.
(10) See the Supporting Information for details.
(11) For another recent example of the formation of palladacycles in C-H
activation processes, see: Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 132, 686.
(12) For the reported high value of the intramolecular KIE in acetoxylation
reactions of 2-arylpyridines (kH/kD ) 5.1), see: (a) Powers, D. C.; Geibel,
M. A. L.; Klein, J. E. M. N.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
17050. Also see: (b) Powers, D. C.; Ritter, T. Nat. Chem. 2009, 1, 302.
(c) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128,
12634.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(13) Presumably, this reaction proceeds via formation of a palladacycle. See
the Supporting Information for details.
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