Letter
Copper-Catalyzed Oxidative Cleavage of Electron-Rich Olefins in
Water at Room Temperature
Daniel J. Lippincott,† Pedro J. Trejo-Soto,†,‡ Fabrice Gallou,§ and Bruce H. Lipshutz*,†
†Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
‡
́
́
Facultad de Química, Departamento de Farmacia, Universidad Nacional Autonoma de Mexico, CDMX, Mexico City 04510,
́
Mexico
§Novartis Pharma AG, CH-4057 Basel, Switzerland
S
* Supporting Information
ABSTRACT: A copper-catalyzed oxidative cleavage of electron-rich olefins into
their corresponding carbonyl derivatives is described as an alternative to ozonolysis.
The scope includes various precursors to aryl ketone derivatives, as well as
oxidations of enol ethers bearing atypical alkyl and dialkyl substitution, the first of
their kind among such metal catalyzed alkene cleavage reactions. The use of an inexpensive copper salt, room temperature
conditions, an aerobic atmosphere, and water as the global reaction medium highlight the green features of this new method.
Associated mechanistic investigations are also presented.
solvents,6 relies upon a readily available and earth abundant
he use of ozone as a stoichiometric reagent for the
metal,7 and involves a simple and safe protocol is still desirable.
Tgeneration of a carbonyl group is a fundamental reaction
Past documentation of many radical processes both
promoted by, and catalytic in, copper suggested its potential
as a mediator of this transformation. It was anticipated to be an
attractive alternative when compared to those metals used
previously (vide supra) due to copper’s low toxicity, control-
lable oxidation states, relative abundance, and cost.8 Since
copper has been previously utilized with substantial success in
oxidations of alcohols to aldehydes and/or ketones,9 it was
reasonable to anticipate its participation in an oxidative
cleavage of alkenes using a peroxide as the stoichiometric
oxidant. Initial experiments, inspired by Shi’s prior report,2
suggested that our micellar catalysis technology (i.e., using
water at rt) might be amenable.
As shown in Table 1, use of either ligated gold or copper
salts, together with a peroxide under micellar catalysis
conditions, led to varying amounts of the desired ketone in
which copper was found to significantly out-perform gold as
the metal (entries 1 vs 2). These reactions were run “open-
flask”, thereby allowing atmospheric oxygen to participate as
needed in the process. Conversely, when the analogous
reaction was run under argon, no conversion of the starting
α-methylstyrene was observed. However, upon addition of
more peroxide (2.00 equiv) and further stirring while open to
air, the same reaction began to produce the expected oxidation
product (entry 3). Switching from a copper(I) to (II) salt was
of little consequence (entries 1 vs 4). Running the reaction
with TBHP under 1 atm of molecular oxygen, likewise, showed
no benefit, and in fact, led to inferior results (entry 5). A
control reaction run exposed to air, but in the absence of
TBHP afforded no reaction (entry 8), while no reaction was
with valuable applications to organic synthesis. Olefin
oxidation reactions in numerous total synthesis campaigns,
past and present, attest to the impact of this simple, yet
powerful transformation. Notwithstanding its time-honored
status in the community, safety and handling issues that
necessitate specific operational needs (e.g., including speci-
alized laboratory equipment for its formation at low temper-
atures) present a less than ideal situation. An equivalent based
on catalysis, however, might obviate these shortcomings,
allowing for a more practical, safe, and user-friendly approach
to this important reaction. Up until recently,1 there were no
reports on methodologies directed specifically to achieve this
conversion. Only within the past few years have such reports
been successfully conducted under catalytic conditions.
In 2006, Shi and co-workers described a gold-catalyzed
oxidative cleavage of simple benzophenone precursors in
water, albeit at 90 °C.2 Later, an organocatalytic approach was
reported utilizing N-hydroxyphthalimide (NHPI or PINO) in
dimethylacetamide at 80 °C, with molecular oxygen as the
oxidant, again providing mainly benzophenone derivatives.3
More recently, in 2015, Xiao et al. disclosed an elegant
methodology based on iron(III) triflate, in hot DCE.4 This
report described a broad scope of substrates leading to
benzaldehyde, acetophenone, and benzophenone derivatives,
although it relied upon the activity of a noncommercially
available pyridine bis-sulfonamide ligand. Moreover, the
conditions appeared not to be compatible with nitrogen
within the chosen substrates. Lastly, in 2016, a photocatalytic
approach employing an aromatic disulfide as catalyst was
described, nearly exclusively leading to benzaldehyde prod-
ucts.5 Thus, a more general methodology that offers room
temperature conditions, avoids use of waste-generating organic
Received: June 17, 2018
© XXXX American Chemical Society
A
Org. Lett. XXXX, XXX, XXX−XXX