Palladium-catalyzed oxygenation of unactivated sp3 C-H bonds

Article abstract of DOI:10.1021/ja046831c

This communication describes a new palladium-catalyzed method for the oxygenation of unactivated sp³ C-H bonds. A wide variety of alkane substrates containing readily available oxime and/or pyridine directing groups are oxidized with extremely

Full text of DOI:10.1021/ja046831c

Published on Web 07/16/2004
Palladium-Catalyzed Oxygenation of Unactivated sp3 C-H Bonds
Lopa V. Desai, Kami L. Hull, and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109-1055
Received May 28, 2004; E-mail: mssanfor@umich.edu
General catalytic methods for the oxidation of unactivated sp3
Scheme 1. Chelate-Directed Oxidation of Pinacalone O-Methyl
Oxime
C-H bonds would find widespread application in synthetic
chemistry.1 The development of such reactions remains challenging
as a result of the strength of these bonds, the susceptibility of the
products toward over-oxidation, and the difficulty of achieving
regioselective functionalization in the context of complex organic
molecules.1 A number of reports have described stoichiometric
Table 1. Selectivity of Unactivated sp3 C-H Bond Oxidationa
chelate-directed alkane activation/oxidation mediated by group 10
metals,2,3 and these reactions have been applied to the functional-
ization of steroids3c-e and to the synthesis of several other natural
products.3a,b More recently, transition-metal-catalyzed procedures
for the oxidation of methane4 and of some more complex alkane
substrates5,6 have been reported; however, these transformations
generally remain limited as a result of their modest substrate scope
and/or harsh reaction conditions.
We have recently described a new Pd-catalyzed approach to the
selective oxidation of arene and benzylic C-H bonds.7 We report
herein that unactiVated sp3 C-H bonds of both oxime and pyridine
substrates undergo highly regio- and chemoselectiVe Pd(II)-
catalyzed oxygenation with PhI(OAc)2 as a stoichiometric oxidant.
The reactivity and selectivity observed in these transformations are
the result of (i) the use of substrates containing chelating functional
groups (which both direct and accelerate unactivated sp3 C-H
activation) and (ii) the exquisite sensitivity of directed C-H
activation to the steric and electronic properties of the alkane
a 1 equiv of substrate (0.12 M), 1.1 equiv of PhI(OAc)2, 5 mol %
substrate.
Pd(OAc)2, 50% AcOH/50% Ac2O, 100 °C, 1.5-3.5 h. b Isolated yields.
Our initial investigations of alkane oxidation focused on the
â-functionalization of pinacalone O-methyl oxime 1 (Scheme 1).
c Isolated as a mixture of oxime E/Z isomers.
This substrate was selected on the basis of its ready availability
from the parent ketone, as well as on precedent that related
molecules undergo stoichiometric C-H activation at Pd(II).2b In
addition, the expected â-oxygenated products (3a-c) can be
converted to carbonyls8 or amines,9 providing an attractive route
to valuable â-hydroxy ketones and â-amino alcohols, respectively.
Gratifyingly, the reaction of 1 with 1.1 equiv of PhI(OAc)2 and 5
mol % Pd(OAc)2 at 100 °C for 5.5 h resulted in sp3 C-H bond
oxidation to afford a mixture of the mono-, di-, and tri-acetoxylated
products 3a-c.10,11 When the stoichiometry of the oxidant was
increased to 4.5 equiv, 3c was obtained as the major product in
59% isolated yield. Notably, R-oxidation was not observed despite
the higher acidity of the R-C-H bonds (which generally increases
reactivity toward electrophilic C-H activation).2a
A series of substituted O-methyl oxime substrates were next
examined to probe the regioselectivity of these transformations.12,13
As summarized in Table 1, substrates 4-6 reacted with 1.1 equiv
of PhI(OAc)2 and 5 mol % Pd(OAc)2 to afford mono-â-oxygenated
products 9-11 in modest to good yields (entries 1-3). Interestingly,
no â-hydride elimination was observed in any of these systems,
presumably due to the rigidity of the palladacyclic intermediates.14
Reactions of substrate 5 (entry 2), which contains multiple possible
sites for directed C-H activation, showed extremely high selectivity
(i) for functionalization of 1° â-C-H bonds in lieu of those at 2°
carbon centers and (ii) for oxidation at the â- rather than at the
γ-position. Substrates 7 and 8, which contain only 2° â- and/or 1°
γ-C-H bonds, provided further confirmation of the high selectivity
of these transformations, as they did not undergo detectable
oxidation under our standard conditions (entries 4 and 5). Notably,
reactivity toward oxidation was also significantly enhanced by
R-branching, as exemplified by the dramatically higher yield
obtained in the reaction of branched substrate 4 versus linear 6
(entries 1 and 3).
The observed regioselectivities can be rationalized on the basis
of the requirements of C-H activation at Pd(II).2,13 For example,
selective oxidation at 1° versus 2° carbon centers likely results from
a strong steric preference for the formation of less hindered 1° Pd
alkyls.2a The high reactivity of â (versus R or γ) C-H bonds reflects
the advantage of forming five-membered palladacycles.2a Finally,
selectivity for oxygenation at R-branched sites is believed to result
from the requirement for a coplanar relationship between the oxime
and the target C-H bond,2 a conformation that is more readily
accessed with increasing R-substitution.
As summarized in Table 2, Pd-catalyzed oxidation of sp3 C-H
bonds was applied to a variety of additional substrates. For example,
the O-methyl oximes of both 2,2-dimethylcyclopentanone and
camphor were efficiently oxygenated to afford 22 and 23 in good
yields (entries 1 and 2). Interestingly, both of these substrates were
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10.1021/ja046831c CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of sp3 C-H Bond Oxygenationa
31 was formed as a single diastereomer, with the OAc substituent
in the equatorial position.15 This result provides strong evidence
that C-H activation (to form a palladacyclic intermediate) and
subsequent oxidative cleavage (via oxidation to Pd(IV) followed
by C-O bond forming reductive elimination)7,16 both proceed with
high levels of stereoselectivity.17
In conclusion, we have demonstrated an efficient method for
Pd-catalyzed oxygenation of unactivated sp3 C-H bonds using
PhI(OAc)2 as a stoichiometric oxidant. These reactions have signifi-
cant potential synthetic utility, particularly as a result of their high
selectivities. Current work is aimed at more fully elucidating the
scope of potential substrates and oxidants as well as gaining further
insights into the mechanisms of these transformations.
Acknowledgment. We thank the University of Michigan for
start up funds and the Camille and Henry Dreyfus Foundation for
a New Faculty Award.
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.
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a 1 equiv of substrate (0.12 M), 1.1-3.2 equiv of PhI(OAc)2, 5 mol %
Pd(OAc)2, in AcOH, 50% AcOH/50% Ac2O, or CH2Cl2, 80-100 °C, 5
min-12 h. b Isolated yields. c Isolated as a mixture of oxime E/Z isomers.
previously deemed unreactive in stoichiometric cyclopalladation
reactions.3e Oximes of 2-methyl cyclohexanone derivatives were
also good substrates for â-oxygenation (entries 3 and 4), and the
rates of these transformations were extremely sensitive to confor-
mational effects. For example, while the reaction of 14 took 1.5 h
at 100 °C, 15 (whose tert-butyl substituent locks the 2-methyl group
into coplanarity with the oxime) was completely oxidized within 5
min under analogous conditions. Pyridine was also an effective
directing group (entries 5-9), and both the 2-tert-butyl and 2-i-
propyl derivatives underwent oxidation to afford tri- and mono-
oxidized products, respectively (entries 5 and 6). Pyridine-directed
oxidation of alkyl groups adjacent to heteroatoms also proved facile,
and 2-methoxy- and 2-(dimethylamino)pyridine were converted to
28 and 29 in good yields. Notably, these transformations offer a
mild and selective approach to the dealkylation of ethers/amines,
as the acetoxy-substituted acetal (28) and aminal (29) products are
susceptible to acid-catalyzed cleavage to unmask free OH or NH2
functionality.8
(6) Other approaches to alkane functionalization: (a) Hinman, A.; Du Bois,
J. J. Am. Chem. Soc. 2003, 125, 11510. (b) Davies, H. M. L.; Beckwith,
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S.; Semple, T. C.; Hartwig J. F. Science 2000, 287, 1995.
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(10) Other Pd(II) salts afforded comparable or lower yields in catalytic sp3
C-H acetoxylation (see Supporting Information, Table S1).
(11) Notably, the analogous OH oxime underwent oxidative cleavage to the
ketone under the reaction conditions, and the ketone showed no reactivity
towards Pd(II)-catalyzed acetoxylation.
(12) Oxime starting materials were typically used as a mixture of E/Z isomers
and were found to equilibrate rapidly under the reaction conditions.
(13) Stoichimetric directed C-H activation at Pd(II) has been reported to require
fully R-alkylated (e.g., tert-Bu-substituted) substrates, while substrates
analogous to 4-6 have typically been considered unreactive in such
transformations (refs 2 and 3).
(14) Clique, B.; Fabritius, C. H.; Couturier, C.; Monteiro, N.; Balme, G. Chem.
Commun. 2003, 272.
(15) Stereochemistry was assigned by standard analysis of the coupling
constants of the hydrogen R to the acetate (see Supporting Information).
(16) Yoneyama, T.; Crabtree, R. H. J. Mol. Catal. A 1996, 108, 35.
(17) The observed stereochemistry is consistent with either (i) initial C-H
activation at the axial position followed by reductive elimination with
inversion of configuration or (ii) equatorial C-H activation followed by
reductive elimination with retention. Experiments aimed at distinguishing
these mechanistic possibilities are currently underway.
Oxidation at 2° carbon centers was also achieved in these systems
after appropriate electronic or steric modification of the substrate.
For example, when a 2° C-H bond was placed R to an activating
ether substituent, Pd-catalyzed oxygenation proceeded in moderate
yield (entry 9). Additionally, the use of structurally rigid trans-
decalone O-methyl oxime (21) enabled functionalization of an
unactivated 2° sp3 C-H bond (entry 10). Interestingly, the product
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