Oxone as an inexpensive, safe, and environmentally benign oxidant for C-H bond oxygenation

Article abstract of DOI:10.1021/ol0530272

This paper describes the application of peroxide-based oxidants in the Pd(OAc)₂-catalyzed acetoxylation and etherification of arene and alkane C-H bonds. Oxone in acetic acid and/or methanol proved particularly effective, and these transformati

Full text of DOI:10.1021/ol0530272

ORGANIC
LETTERS
2006
Vol. 8, No. 6
1141-1144
Oxone as an Inexpensive, Safe, and
Environmentally Benign Oxidant for
C−H Bond Oxygenation
Lopa V. Desai, Hasnain A. Malik, and Melanie S. Sanford*
UniVersity of Michigan, Department of Chemistry, 930 North UniVersity AVenue,
Ann Arbor, Michigan 48109-1055
mssanfor@umich.edu
Received December 14, 2005
ABSTRACT
This paper describes the application of peroxide-based oxidants in the Pd(OAc)2-catalyzed acetoxylation and etherification of arene and alkane
H bonds. Oxone in acetic acid and/or methanol proved particularly effective, and these transformations were applied to a wide variety of
C
−
substrates.
The development of selective and efficient catalytic methods
for the oxidation of organic molecules remains a significant
challenge in synthetic chemistry. In particular, oxidation
reactions that utilize environmentally benign and inexpensive
using PhI(OAc)2 as a terminal oxidant. These ligand-directed
reactions typically proceed in good yields and with high
levels of regioselectivity; however, they suffer from signifi-
cant disadvantages: the iodine(III) oxidant is expensive
(∼$1/g)7 and forms stoichiometric quantities of toxic PhI
with each catalytic turnover. As such, an ongoing goal in
our group has been the development of C-H bond oxygen-
ation reactions that utilize more desirable organic or inorganic
peroxides as terminal oxidants.8
5
peroxides1-4 and/or O2 as stoichiometric oxidants are
extremely attractive, as they render the resulting transforma-
tions “greener” and more practical for large-scale synthesis.
We have recently described a new method for the Pd-
catalyzed oxygenation of arene6b,c and alkane6a C-H bonds
Our approach to this challenge began with a careful
consideration of the mechanism of the Pd-catalyzed C-H
bond oxidation. Our previous work suggested that the key
carbon-oxygen coupling step involves C-O bond-forming
reductive elimination from a PdIV acetoxy intermediate of
general structure 1 (Scheme 1).6,9 When PhI(OAc)2 is used
as the oxidant in an organic solvent, the OAc ligand of 1
(1) For reviews on hydrogen peroxide as a terminal oxidant in catalysis,
see: (a) Noyori, R.; Aoki, M.; Sato, K. Chem. Commun. 2003, 1977. (b)
Jones, C. W. Applications of Hydrogen Peroxide and DeriVatiVes; Royal
Society of Chemistry: Cambridge, 1999. (c) Catalytic Oxidations with
Hydrogen Peroxide as Oxidant; Strukul, G., Ed.; Kluwer Academic:
Dordrecht, 1992.
(2) For recent examples of the use of peracetic acid as an oxidant in
catalysis, see: Murphy, A.; Pace, A.; Stack, T. D. P. Org. Lett. 2004, 6,
3119 and references therein.
(3) For recent examples of the use of Oxone as a stoichiometric oxidant
in catalytic reactions, see: (a) Yang, D. Acc. Chem. Res. 2004, 37, 497
and references therein. (b) Schomaker, J. M.; Travis, B. R.; Borhan, B.
Org. Lett. 2003, 5, 3089 and references therein. (c) Travis, B. R.; Narayan,
R. S.; Borhan, B. J. Am. Chem. Soc. 2002, 124, 3824.
(4) For examples of the use of K2S2O8 in the Pd-catalyzed C-H
activation/oxygenation of methane, see: (a) Muehlhofer, M.; Strassner, T.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1745. (b) Gretz, E.;
Oliver, T. F.; Sen, A. J. Am. Chem. Soc. 1987, 109, 8109.
(6) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 9542. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (c) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996,
108, 35.
(7) Aldrich Chemical Catalog, 2005.
(8) While the current manuscript was in preparation, the use of organic
peroxyesters as oxidants for Pd-catalyzed oxygenation reactions was
reported. Giri, R.; Liang, J.; Lei, J. G.; Li, J. J.; Wang, D. H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J. Q. Angew. Chem., Int. Ed.
2005, 44, 7420.
(9) Dick, A. R.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005,
127, 12790.
(5) For recent reviews on the use of O2 as a stoichiometric oxidant in
catalysis, see: (a) Stahl, S. S. Science 2005, 309, 1824. (b) Stahl, S. S.
Angew. Chem., Int. Ed. 2004, 43, 3400.
10.1021/ol0530272 CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/11/2006

Scheme 1. C-H Bond Oxygenation Using PhI(OAc)2 or
Table 1. Use of Peroxide-Based Oxidants in the
Pd(OAc)2-Catalyzed C-H Bond Oxygenation
Peroxides as Terminal Oxidants
isolated
yield (%)
of 2aa
isolated
yield (%)
of 2aa
entry
oxidant
H2O2‚urea
50% aq H2O2
m-CPBA
entry oxidant
1
2
3
4
10
11
14
18
5
6
7
8
CH3CO3H
Oxone
K2S2O8
34
68
76b
81b
70% aq t-BuOOH
PhI(OAc)2
a Conditions: 5 mol % Pd(OAc)2, 2 equiv of oxidant, 0.12 M 2 in AcOH/
Ac2O (50:50), 100 °C, 12 h; 2a isolated as a 5:1 mixture of oxime E/Z
isomers and as a >20:1 mixture of regioisomers. b Between 10 and 15%
of the di-o-acetoxylated product was also isolated.
(which ultimately ends up in the product) is derived from
the iodine(III) oxidant (Scheme 1a).9
However, we reasoned that the key PdIV intermediate 1
might be accessed using alternative peroxide-based oxidants
if the reactions were conducted in the presence of an external
acetate source such as acetic acid (Scheme 1b). This
hypothesis was predicated on the fact that platinum(IV)
analogues of 1 can be prepared by treatment of PtII complexes
with either PhI(OAc)2 in CH2Cl210 or with hydrogen peroxide
in AcOH (eq 1).11 Importantly, such PtIV adducts are
frequently considered to be stable model complexes for
transient PdIV catalytic intermediates,12 suggesting that
analogous conditions (peroxides in AcOH) might be used
to generate the key intermediate 1 in Pd-catalyzed transfor-
mations.
5 mol % of Pd(OAc)2, 100 °C, 12 h), Oxone and K2S2O8
performed best, providing 2a in 68% and 76% isolated yield,
respectively. These yields were only slightly lower than those
obtained with PhI(OAc)2 under otherwise identical reaction
conditions.
Carbon-hydrogen bond oxygenation reactions with Oxone
are particularly attractive because they can be easily, safely,
and inexpensively scaled. For example, the acetoxylation of
2 proceeds cleanly and efficiently when carried out with 15
g of substratesan approximately 100-fold increase in scale
from the initially optimized reaction conditions (eq 2).
Product 2a was readily isolated via Kugelrohr distillation in
54% yield. Notably, the large-scale reaction was conducted
using just 3 mol % of Pd(OAc)2, and the catalyst loading
could potentially be reduced even further, albeit with longer
reaction times.
Our initial investigations to test this hypothesis focused
on the Pd(OAc)2-catalyzed acetoxylation of oxime ether
2 with a variety of peroxide oxidants in AcOH/Ac2O (Table
1).13 We were delighted to discover that all of the per-
oxides examined (including hydrogen peroxide,14 peracetic
acid, K2S2O8, and Oxone) produced significant quantities of
the o-acetoxylated product 2a. Under standard reaction
conditions (0.12 M 2 in AcOH/Ac2O,13 2 equiv of oxidant,
The scope of the Pd(OAc)2-catalyzed C-H bond acetoxy-
lation with Oxone and/or K2S2O8 in AcOH was next
15
examined with a diverse array of organic substrates. As
summarized in Table 2, these transformations could be
applied to compounds containing a variety of different
directing groups, including oxime ethers of both ketones
(entries 1-7, 12, 13) and aldehydes (entries 8, 9), amides
(entry 10), and isoxazolines (entry 11).16 The reactions
generally proceeded in comparable or moderately lower
yields than with PhI(OAc)2 under otherwise identical reaction
conditions. The acetoxylation of aromatic C-H bonds with
these inorganic peroxides proceeded efficiently in arene
(10) Barnard, C. F. J.; Vollano, J. F.; Chaloner, P. A.; Dewa, S. Z. Inorg.
Chem. 1996, 35, 3280.
(11) For example, see: Lee, Y.-A.; Yoo, K. H.; Jung, O.-S. Bull. Chem.
Soc. Jpn. 2003, 76, 107.
(12) For recent examples of the use of Pt compounds as models for Pd
catalytic intermediates, see: (a) Dick, A. R.; Kampf, J. W.; Sanford, M. S.
Organometallics 2005, 24, 482. (b) Canty, A. J.; Denney, M. C.; van Koten,
G.; Skelton, B. W.; White, A. H. Organometallics 2004, 23, 5432. (c) Canty,
A. J.; Patel, J.; Rodemann, T.; Ryan, J. H.; Skelton, B. W.; White, A. H.
Organometallics 2004, 23, 3466.
(13) In general, comparable yields of oxygenated products were obtained
with or without added acetic anhydride. However, without this additive,
some hydrolysis of the OAc group of the product was often observed under
the reaction conditions.
(14) The modest reactivity of H2O2 in the catalytic reactions (despite its
ability to stoichiometrically oxidize PtII complexes) may be due to the
tendency for H2O2 to undergo disproportionation in the presence of PdII
salts. For a detailed discussion of such disproportionation reactions, see:
Steinhoff, B. A.; Fix, S. R.; Stahl, S. S. J. Am. Chem. Soc. 2002, 124, 766.
(15) For most substrates, Oxone and K2S2O8 afforded similar results;
however, in some cases (e.g., the sp3 substrates) significantly better yields
were obtained with K2S2O8. The reasons for this difference in reactivity
are unclear at this time and are currently under investigation.
1142
Org. Lett., Vol. 8, No. 6, 2006

was obtained in the acetoxylation of phenol substrate 9 with
Oxone as a terminal oxidant, while the analogous reaction
with PhI(OAc)2 afforded <5% of the product 9a.
Table 2. Pd(OAc)2-Catalyzed Acetoxylation of C-H Bonds
In most substrates containing a meta substituent on the
aromatic ring (Table 2, entries 2-8), modest to high
selectivity was observed for acetoxylation of the less
sterically hindered o-C-H bond.17 The levels of regioselec-
tivity in these transformations ranged from ∼1.6:1 for a m-F
substituent to >20:1 for the m-Br and m-CF3 groups.
Importantly, nearly identical selectivities were obtained with
PhI(OAc)2 under the same conditions, consistent with a
mechanism in which the selectivity is determined by the
initial C-H activation step and is therefore unaffected by
the nature of the terminal oxidant. A notable exception to
the observed trends was the m-hydroxyl-substituted oxime
ether 9, which underwent Pd(OAc)2-catalyzed reaction with
Oxone to afford the 1,2,3-trisubstituted arene 9a as the sole
observed regioisomeric product. While the origin of this
unusual selectivity remains under investigation, it might result
from a combination of the relatively small size and the strong
coordinating ability of the OH substituent.
The activation and subsequent oxidative functionalization
of unactivated sp3 C-H bonds typically represents a
significantly greater challenge than the analogous reactions
of arene derivatives.4,6a,8 Therefore, it is particularly notable
that alkane substrates 14 and 15 also underwent Pd(OAc)2-
catalyzed acetoxylation with inorganic peroxides in AcOH
(Table 2, entries 12 and 13). Both Oxone and K2S2O8 could
be utilized as terminal oxidants for these transformations,
although better isolated yields were obtained with K2S2O8.15
Substrate 14 is particularly noteworthy, as it contains 6
diverse types of sp3 carbon-hydrogen bonds. Similar to
reactions with PhI(OAc)2,6a a single acetoxylated product 14a
was obtained in which a primary â-C-H bond was func-
tionalized, despite the presence of both weaker (secondary
and tertiary) as well as more acidic (enolic) C-H bonds.
This result indicates that competing free radical pathways
(which are well-precedented with K2S2O8)18 are negligible
under our reaction conditions.
We next turned our attention to expanding the use of
peroxide-based oxidants to other Pd(OAc)2-catalyzed C-H
(16) One limitation of peroxide-based oxidants with respect to substrate
scope is their tendency to promote competitive N-oxidation of some basic
nitrogen-based directing groups. This is exemplified by the reaction of
8-methylquinoxoline shown below.
a Conditions: 5 mol % Pd(OAc)2, 1-2 equiv of Oxone, 0.12 M in AcOH
or AcOH/Ac2O, 100 °C, 12 h. Major regioisomer and oxime E/Z isomer of
product is shown where relevant. b Conditions: 5 mol % Pd(OAc)2, 1.1-
1.3 equiv of PhI(OAc)2, 0.12 M in AcOH or AcOH/Ac2O. c K2S2O8 used
as the oxidant. d 3 equiv of oxidant.
substrates containing both electron-withdrawing (entries 4-6)
and electron-donating (entries 2, 3, 7-9) substituents.
Furthermore, a wide variety of functional groups, including
aryl halides, nitriles, ethers, enolizable oxime ethers and
amides, and benzylic C-H bonds were tolerated under the
oxidizing reaction conditions. In fact, in some cases, Oxone
showed substantially improved functional group tolerance
relative to PhI(OAc)2. For example, a modest (37%) yield
(17) For a detailed investigation of regioselectivity in Pd(OAc)2-catalyzed
C-H bond acetoxylation with PhI(OAc)2, see: Kalyani, D.; Sanford, M.
S. Org. Lett. 2005, 7, 4149.
(18) For examples of C-H bond functionalization reactions initiated by
K2S2O8 that proceed through free radical mechanisms, see: (a) Lobree, L.
J.; Bell, A. T. Ind. Eng. Chem. Res. 2001, 40, 736. (b) Asadullah, M.;
Kitamura, T.; Fujiwara, Y. Appl. Organomet. Chem. 1999, 13, 539. (c)
Basickes, N.; Hogan, T. E.; Sen, A. J. Am. Chem. Soc. 1996, 118, 13111.
Org. Lett., Vol. 8, No. 6, 2006
1143

bond functionalization reactions. Based on the mechanistic
discussions above (Scheme 1 and eq 1), we reasoned that
changing the reaction solvent from AcOH to MeOH might
result in the formation of PdIV alkoxide intermediates
analogous to 1 (e.g., complex 1a, eq 3), which could undergo
C-O bond-forming reductive elimination to afford ether
products.6b Again, this hypothesis was supported by the
known chemistry of inorganic platinum(IV) complexes,
which serve as potential models for highly reactive PdIV
intermediates.12a,19 For example, as summarized in eq 3, PtII
starting materials are well-known to react with H2O2 in
methanol to afford stable PtIV dialkoxides in good yields.19
Table 3. Pd(OAc)2-Catalyzed Formation of Aryl Ethers with
Oxone or K2S2O8 in Methanol
Our initial attempts to form ether products focused on the
Pd-catalyzed reaction of oxime ether 2 with Oxone in
methanol. Gratifyingly, this transformation cleanly afforded
aryl methyl ether 2b in 70% isolated yield (Table 3, entry
1). Notably, this and related ether-forming reactions required
careful temperature regulation (with a gradual ramp from
room temperature to between 40 and 80 °C) to avoid
irreversible formation of palladium black (presumably via
reduction of PdII by the alcohol solvent). However, under
these carefully controlled conditions, Pd(OAc)2-catalyzed
C-H bond methoxylation with Oxone or K2S2O8 could be
applied to several different unsubstituted, ortho-substituted,
and meta-substituted arene substrates. Furthermore, as sum-
marized in Table 3, these reactions exhibited comparable
functional group tolerance and reaction yields to the peroxide-
mediated acetoxylation reactions described above.
In conclusion, we have demonstrated that mechanistic
considerations in conjunction with platinum(IV) model
complexes have led to the development of new Pd(OAc)2-
catalyzed C-H bond oxygenation reactions that utilize
peroxides as stoichiometric oxidants. Inexpensive, safe, and
environmentally benign Oxone was found to be a particularly
effective terminal oxidant in these transformations and
exhibited functional group tolerance and substrate scope that
was comparable (and, in some cases, complementary) to PhI-
(OAc)2. Our ongoing work in this area seeks to further
expand the scope and functional group tolerance as well as
to gain further insights into the mechanisms of these
peroxide-mediated reactions.
a Conditions: 5-10 mol % Pd(OAc)2, 2-3 equiv of Oxone, 0.12 M in
MeOH, 25 °C to between 40 and 80 °C over 48 h. Major regioisomer and
oxime E/Z isomer is shown (where relevant). b K2S2O8 used as the oxidant.
Acknowledgment. We thank the NIH NIGMS (RO1-
GM073836-01), the University of Michigan, the Camille and
Henry Dreyfus Foundation, and the Arnold and Mabel
Beckman Foundation for support of this work. Unrestricted
support from Amgen, Boehringer Ingelheim, and Eli Lilly
as well as a gift of PhI(OAc)2 from Merck are also gratefully
acknowledged. L.V.D. thanks Bristol Myers Squibb for a
graduate fellowship. In addition, we gratefully acknowledge
Dipa Kalyani for assistance with NMR characterization of
the products and Waseem Anani for carrying out the
oxidation of 8-methylquinoxoline with PhI(OAc)2.
Supporting Information Available: Experimental details
and spectroscopic and analytical data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For example, see: Lee, Y.-A.; Jung, O.-S. Bull. Chem. Soc. Jpn.
2002, 75, 1533.
OL0530272
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Org. Lett., Vol. 8, No. 6, 2006