Double-fold C-H oxygenation of arenes using PyrDipSi: A general and efficient traceless/modifiable silicon-tethered directing group

Article abstract of DOI:10.1021/ja3010545

The efficient Pd-catalyzed double-fold C-H oxygenation of arenes into resorcinols using the newly developed 2-pyrimidyldiisopropylsilyl (PyrDipSi) directing group is described. Its use allows for the sequential introduction of OAc and OPiv groups in a one-pot manner to produce orthogonally protected resorcinol derivatives. The PyrDipSi group is superior to the previously developed 2-pyridyldiisopropylsilyl (PyDipSi) group, as it is efficient for monooxygenation of ortho-substituted arenes. Notably, the PyrDipSi group can be easily installed into arene molecules and can be easily removed or modified after the oxygenation reaction.

Full text of DOI:10.1021/ja3010545

Communication
pubs.acs.org/JACS
Double-Fold C−H Oxygenation of Arenes Using PyrDipSi: a General
and Efficient Traceless/Modifiable Silicon-Tethered Directing Group
Anton V. Gulevich, Ferdinand S. Melkonyan, Dhruba Sarkar, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
Although selected examples of double C−H acetoxylation of
ABSTRACT: The efficient Pd-catalyzed double-fold
C−H oxygenation of arenes into resorcinols using the
newly developed 2-pyrimidyldiisopropylsilyl (PyrDipSi)
directing group is described. Its use allows for the sequential
introduction of OAc and OPiv groups in a one-pot manner to
produce orthogonally protected resorcinol derivatives. The
PyrDipSi group is superior to the previously developed 2-
pyridyldiisopropylsilyl (PyDipSi) group, as it is efficient for
monooxygenation of ortho-substituted arenes. Notably, the
PyrDipSi group can be easily installed into arene molecules
and can be easily removed or modified after the oxygenation
reaction.
arenes using nonremovable directing groups, such as
pyridine,8a,f pyrazole8f or ketoxime,8h were reported by Sanford
and co-workers, the use of a cleavable/functionalizable directing
group could significantly increase the synthetic applicability of
the method. Herein we report the 2-pyrimidyldiisopropylsilyl
(PyrDipSi) group, an efficient, easily removable/modifiable
directing group for efficient Pd-catalyzed double C−H
oxygenation of arenes into resorcinol derivatives (eq 2).
As reported earlier,7a the pyridine-based PyDipSi group pro-
duces monoacetoxylated product A in 80% yield with no double
oxygenation product observed (Scheme 1). We envisioned that
Scheme 1. Optimization of the Directing Group (DG)
ransition-metal-catalyzed C−H functionalization reactions
T
represent a very powerful tool for straightforward modi-
fication of various organic molecules.1 Among these reactions,
C−H functionalization of arenes can be efficiently used for
formation of new carbon−carbon2 and carbon−heteroatom3
bonds. However, most directing groups cannot be easily re-
moved from the molecule after C−H functionalization, thus
limiting this methodology to a particular type of substrate.
Therefore, the use of removable directing groups4 could dra-
matically increase the synthetic applicability of C−H fun-
ctionalization processes.5 Thus, Itami and Yoshida employed a
Si-tethered pyridine group as a removable directing group for
Heck and Pauson−Khand-type reactions.6 Using this concept,
we recently developed the pyridine-based 2-pyridyldiisopro-
pylsilyl (PyDipSi) group7 as a removable directing group for
the Pd-catalyzed mono C−H oxygenation8 reaction of arenes
(eq 1). Feasibly, double C−H oxygenation could provide access
the use of a heterocycle with two heteroatoms as a directing group
may facilitate the second C−H insertion reaction. Hence, we ex-
plored different Si-tethered heterocycles, including thiazole,10 benzo-
thiazole, imidazole, N-methylimidazole,10 and pyrimidine,8h,11 as
potential directing groups under previously reported acetoxylation
reaction conditions.7a It was found that thiazole- and imidazole-
based directing groups were not efficient at all. To our delight, the
pyrimidine-based PyrDipSi group showed promising results, produc-
ing the desired bisacetoxylated product 2a in 26% yield (Scheme 1).
Next, optimization of the double oxygenation of PyrDipSi-
benzene (1a) was performed (Table 1). Upon screening additives,
we found that the combination of LiCl and AgOAc produced
2a in 90% yield. Finally, LiOAc (30%) was found to be the most
efficient additive, providing 2a in almost quantitative GC yield
(entry 11). However, because of its low stability toward column
chromatography, we obtained a diminished isolated yield of
2a (87%). Gratifyingly, the pivaloxylation reaction using
PhI(OPiv)2 under these reaction conditions produced the
corresponding chromatography-stable bispivaloxylated
product 3a in almost quantitative yield (entry 11). Notably,
to resorcinol derivatives, which are valuable building blocks for
synthesis, medicinal chemistry, and materials science.9
Received: February 1, 2012
Published: March 13, 2012
© 2012 American Chemical Society
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a
a
Table 1. Optimization of the Double Oxygenation Reaction
Table 2. Double Pivaloxylation of PyrDipSiAr
a
Conditions: 1a (0.1 mmol), catalyst, oxidant, and additive in 0.25 mL
of DCE (0.4 M) were stirred at 80 °C in a sealed vial under a N2 atmo-
sphere. GC yields are given. Isolated yields are given in parentheses.
b
c
Concentration 1 M. 3 mmol scale.
these optimized reaction conditions feature a lower amount of
oxidant (1.25 equiv) and a lower catalyst loading as well as
inexpensive LiOAc as a cocatalyst. The use of LiOAc was found
to be crucial for the successful second C−H oxygenation, which
could indicate that the reaction follows a concerted metal-
ation−deprotonation (CMD) pathway.12
We also developed a simple and scalable procedure for installa-
tion of PyrDipSi onto aryl iodides. First, PyrDipSiH was prepared
from 2-iodopyrimidine and commercially available diisopropyl-
chlorosilane. Thus, formation of the pyrimidylmagnesium com-
pound13 followed by reaction with the chlorosilane afforded
PyrDipSiH in high yield. Subsequent Rh-catalyzed coupling of aryl
iodides with PyrDipSiH provided a number of PyrDipSi arenes 1
in good yields (Scheme 2).14
a
b
0.2 mmol scale; isolated yields are given. 10% cat.
substituent at the meta position, underwent the double oxy-
genation reaction to give resorcinol 3p, although in dimin-
ished yield (entry 16).
Next, we aimed at achieving nonsymmetrical bisfunctional-
ization of PyrDipSi arenes via a sequential C−H acetoxylation/
pivaloxylation reaction (Scheme 3). Thus, acetoxylation of 1a
Scheme 2. Installation of the PyrDipSi Group
Scheme 3. Nonsymmetric Double-Fold C−H Oxygenation
With an efficient method for installation of the PyrDipSi
group and optimized conditions for double pivaloxylation in hand,
we investigated the scope of the reaction (Table 2). It was found
that a variety of arenes bearing alkyl or aryl substituents produced
the corresponding resorcinol derivatives in excellent yields. More-
over, different functional groups, such as methoxy (entry 6),
carbomethoxy (entry 7), amide (entry 8), and acetyl (entry 9),
were also tolerated. Notably, formyl (entry 10) and styryl
(entry 11) groups, which are prone to oxidation, furnished the
corresponding products in good yields. All halogens were com-
patible with the reaction conditions (entries 12−15), thus provid-
ing compounds bearing an additional handle for a subsequent
functionalization.15 Because of the additional steric hindrance,
3-substituted PyrDipSi arenes exhibited substantially lower re-
activities. Thus, only PyrDipSi-benzene 1p, possessing a small F
with PhI(OAc)2 followed by a one-pot pivaloxylation reaction of
the intermediate using PhI(OPiv)2 in the presence of LiOAc
(30%) furnished the corresponding product 4a in good yield.
This protocol enabled the preparation of differently substituted,
orthogonally protected resorcinol derivatives 4a−c in good yields.
As expected, the acetyl group could be selectively cleaved in the
presence of the pivaloxy group, thus producing monoprotected
resorcinol derivative 4b′ in high yield (Scheme 3).
We also investigated the monopivaloxylation reaction of
ortho-substituted PyrDipSi arenes (Scheme 4). It was found
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usefulness of the developed methodology is further illustrated
by the efficient three-step conversion of 4-iodobromobenzene
into the corresponding resorcinol 8c (Scheme 5).16
Scheme 4. Pivaloxylation of Ortho-Substituted PyrDipSiAr
In conclusion, we have developed PyrDipSi, a new general and
efficient silicon-tethered directing group that can be easily installed
on aryl iodides by Rh-catalyzed coupling with PyrDipSiH. The use
of this new directing group enabled the mild and efficient Pd-
catalyzed double C−H oxygenation of arenes, producing valuable
resorcinol derivatives. Moreover, the developed convenient
protocol for the one-pot acetoxylation/pivaloxylation reaction is
efficient for the synthesis of orthogonally protected resorcinols.
In contrast to the previously developed PyDipSi group, the
PyrDipSi group is also efficient for monooxygenation of ortho-
substituted arenes. Finally, we have shown that this new directing
group can be easily removed or converted to valuable aryl iodides.
that various ortho-substituted PyrDipSi arenes 1q−w underwent
smooth pivaloxylation, producing the corresponding products 5
in good yields. Thus, methoxy (entry 5a) and methyl (entries
5b and 5c) as well as fluorine (entry 5d), chlorine (entry 5e),
and bromine (entry 5f) were tolerated at the ortho position of
the arene. Likewise, 1-PyrDipSi-naphthalene afforded the cor-
responding product 5g in good yield. In contrast, the previously
developed PyDipSi group did not appear to be efficient at all
in the oxygenation of ortho-substituted arenes. Thus, o-Br-
PyDipSi-benzene, under the same reaction conditions, did not
produce detectable amounts of oxygenated product 5f′, the
PyDipSi analogue of 5f (Scheme 4).16 Although at this point the
dramatic difference in the directing abilities of the PyrDipSi and
PyDipSi groups remains unclear, it is most likely attributable to
the different basicity/binding properties of these groups.17
Finally, we showed that the PyrDipSi group can be easily re-
moved from the bisoxygenated products 4 to provide the corres-
ponding protected resorcinols 6 or deuterated analogues 7 in almost
quantitative yields (Scheme 5). Moreover, the PyrDipSi group can
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
vlad@uic.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NIH (GM-64444) for financial support.
■
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(17) Sanford and co-workers did not observe a strong correlation
between directing ability and basicity (for directing groups of different
sizes) in the Pd-catalyzed C−H oxygenation reaction.8h Here,
however, because of the steric similarity of PyrDipSi and PyDipSi,
their basicity18 could play a role in the reaction. Also, we observed that
even catalytic amounts of pyridine suppress the second C−H
oxygenation reaction (Table 1, entry 3). For the influence of the
electron-withdrawing nature of pyrimidine on the Pd-catalyzed C−H
trifluoromethylation reaction, see ref 10.
(18) Rewcastle, G. W. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R.,; Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier: Oxford, U.K., 2008; Vol. 8.02, p 123.
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