A mild, catalytic, and highly selective method for the oxidation of α,β-enones to 1,4-enediones

Article abstract of DOI:10.1021/ja0340735

A new and simple method is described for the one-step oxidation of α,β-enones to 1,4-enediones in good yields (generally 80-90%) using t-butylhydroperoxide as stoichiometric oxidant and 20% Pd(OH)₂ on carbon (5 mol %) as catalyst in CH₂Cl₂ solution. The same reagents have been used to convert ethylene ketals of α,β-enones to the corresponding monoethylene ketals of 1,4-enediones. Seven representative examples are presented in Table 1. All of the available evidence on these oxidations points to a radical-chain mechanism initiated by the tert-butylperoxy radical (see Scheme 1). γ-tert-Butylperoxy ethers are formed as major products in the oxidation of α,β-enones possessing only a single γ-hydrogen. Copyright

Full text of DOI:10.1021/ja0340735

Published on Web 02/21/2003
A Mild, Catalytic, and Highly Selective Method for the Oxidation of
r,â-Enones to 1,4-Enediones
Jin-Quan Yu† and E. J. Corey*,‡
Department of Chemistry, Cambridge UniVersity, Cambridge CB2 1EW, United Kingdom, and
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received January 8, 2003 ; E-mail: corey@chemistry.harvard.edu
Table 1. Synthesis of 1,4-Enediones
The position-selective replacement of hydrogen by oxygen results
in an increase of molecular complexity, specifically, a gain in
reactive functionality that is very useful in multistep synthesis. We
describe herein a new, practical, and very mild method for the
conversion of an enone subunit, -(CO)-CHdCH-CH2-, to the
corresponding 1,4-enedione, -(CO)-CHdCH(CO)-. To the best
of our knowledge, there is no other general method for effecting
this conversion. The 1,4-enedione system is found in a variety of
bioactive natural products including marine natural products,1
sesquiterpenes,2 steroids,3 antitumor agents,4 antifungal agents,5 and
insect toxins, for example, (E)-non-3-ene-2,5-dione (1), an important
toxic component of the fire bee Trigona tataira.6 In addition, by
virtue of their electrophilicity and electron affinity, 1,4-enediones
serve as excellent substrates for further synthetic elaboration. They
have been used, for example, as highly reactive dienophiles for
the construction of complex fused ring systems by Diels-Alder 2
+ 4 cycloaddition7 and as Michael acceptors.8
The oxidation reagent which we have developed for the synthesis
of 1,4-enediones consists of a mixture of 5 equiv of tert-butyl-
hydroperoxide (stoichiometric oxidant), 5 mol % of 20% Pd(OH)2
on carbon (Pearlman’s catalyst; Aldrich Co.),9 and 0.25 equiv of
K2CO3 in methylene chloride at 4 °C or room temperature (24 °C),
depending on the substrate. Although Pd(OH)2-on-carbon is
normally used as a hydrogenation catalyst rather than as a catalyst
for oxidation, in this case, it serves to initiate reaction by a
remarkable activation of t-BuOOH. Under these conditions, a
variety of R,â-enones are smoothly oxidized in good yield to the
corresponding 1,4-enediones, as documented in Table 1. Also shown
in Table 1 are two cases (entries 3 and 4) in which a ketal of an
R,â-enone is oxidized to a monoketal of a 1,4-enedione. These
examples are especially interesting not only because the method
of synthesis outlined in Table 1 is both simple and advantageous,
but also because the corresponding enediones are sensitive and not
easily made.10 As shown in entry 7 of Table 1, the new 1,4-enedione
synthesis provides a simple route to the fire bee toxin 16 and its
homologues.
a Pd(OH)2-C pretreated with t-BuOOH; otherwise 10 equiv of t-BuOOH
is required to achieve 82% yield.
chromatography on silica gel (using hexanes-ether for elution) or
by distillation in vacuo.12 An alternative procedure, which may in
some cases be advantageous, involves the pretreatment of Pd(OH)2-
on-carbon with t-BuOOH in CH2Cl2 at 24 °C with stirring for 1 h.
Under these conditions, the initial rate of the oxidation reaction is
faster, and, for example, for entry 5 in Table 1, a shorter reaction
and a smaller excess of t-BuOOH can be used.13 We believe that
this method constitutes an advantageous route to 1,4-enediones from
R,â-enones in comparison to the use of other reagents which have
been reported for such oxidations in a handful of cases (specifically
pyridinium dichromate in DMF14a or CrO3 in HOAc14b and
tetrazolium salts15). It is also simpler than a variety of multistep
routes which have been reported previously for accessing 1,4-
enedione systems.16
The experimental procedures for the oxidations shown in Table
1 are extremely simple. After the reactants were stirred in CH2Cl2
until thin layer chromatographic analysis shows complete consump-
tion of the starting R,â-enone or monoketal,11 the palladium on
carbon catalyst is removed by filtration, the solvent is evaporated
under reduced pressure, and the product is isolated either by flash
R,â-Unsaturated esters are also transformed into γ-oxo deriva-
tives using the conditions of Table 1 as shown for the conversion
of 2 f 3. Accompanying 3 in this case is a small amount of the
† Cambridge University.
‡ Harvard University.
9
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J. AM. CHEM. SOC. 2003, 125, 3232-3233
10.1021/ja0340735 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
product of oxidative attack at C(R) (4). Significantly, γ-tert-
butylperoxy ethers are formed as major products in the oxidation
In our judgment, the selectivity, simplicity, and practicality of
the new oxidation methodology described herein will encourage
and facilitate the wider use of highly reactive 1,4-enediones as
intermediates for the construction of more complex molecules.
Acknowledgment. We are grateful to Pfizer Inc. for generous
research support and also to St. John’s College, Cambridge
University, for a Research Fellowship to J.-Q.Y.
of R,â-enones possessing only a single γ-hydrogen, as shown for
the examples 5 f 6 and 8 f 9. In the oxidation of 5, the γ-hydroxy-
R,â-enone 7a is also formed (ca. 20%) along with a small amount
of the corresponding hydroperoxide 7b (ca. 4%) (isolated and
characterized). Under the conditions for the oxidation of 5, 7b
undergoes conversion to 7a and clearly is a transient intermediate.
Supporting Information Available: Experimental procedures and
physical data for the reactions summarized in Table 1 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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We have made a number of observations that are relevant to the
mechanism of the Pd-promoted synthesis of 1,4-enediones which
is disclosed herein. As reported earlier, various Pd(II) compounds
and K2CO3 are capable of generating the tert-butylperoxy radical
(t-BuOO‚) from tert-butylhydroperoxide.17 One indication of this
is the generation of O2 from mixtures of Pd(II) compounds, K2-
CO3, and t-BuOOH, which can be accounted for by dimerization
of t-BuOO‚ to di-tert-butyltetroxide.18,19 Evolution of O2 is also
observed with Pd(OH)2-on-C, K2CO3, and t-BuOOH under condi-
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formation of t-BuOO‚ would seem to be electron transfer from
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radical initiated conversion of R,â-enones to 1,4-enediones is shown
in Scheme 1. Although the exact nature of the lower valent PdX
(11) In the event that an oxidation reaction does not progress to completion,
more Pd(OH)2-on-C should be added.
(12) The following procedure used for the monoethylene ketal of 2-cyclopenten-
1,4-dione (Table 1, entry 3). A 25 mL round-bottom flask equipped with
a stir bar was charged with 20% Pd(OH)2- (17 mg, 0.032 mmol Pd),
K2CO3 (11 mg, 0.08 mmol), 1 mL of CH2Cl2, and 2-cyclopenten-1-one
ethylene ketal (76 µL, 0.64 mmol). The mixture was cooled to 4 °C with
an ice bath, and TBHP (160 µL, 1.6 mmol) was added with vigorous
stirring. The flask was sealed (without removal of air) with a rubber septum
and allowed to warm to 24 °C, and the contents were stirred for 24 h at
which time an additional 8.5 mg of 20% Pd(OH)2-C (0.016 mmol), 5.5
mg of K2CO3 (0.04 mmol), and 80 µL of t-BuOOH (0.8 mmol) were
added. The reaction mixture was stirred at 24 °C for another 24 h, and a
third batch of 8.5 mg of 20% Pd(OH)2-C (0.016 mmol), 5.5 mg of K2-
CO3 (0.04 mmol), and 80 µL of t-BuOOH (0.8 mmol) was added. After
an additional 24 h at 24 °C, thin layer chromatographic analysis indicated
that the reaction was complete. Filtration, removal of solvent from the
filtrate, and flash chromatography on a column of silica gel (1.5:1
hexanes-ether for elution) afforded 72 mg (80%) of 2-cyclopenten-1,4-
dione monoethylene ketal as a colorless liquid. 1H NMR 400 MHz,
CDCl3): δ 7.21 (d, J ) 6.2 Hz, 1H), 6.20 (d, J ) 6.2 Hz, 1H), 4.06 (m,
4H), 2.61 (s, 2H). 13C NMR (400 Hz, CDCl3): δ 203.9, 156.2, 135.3,
111.6, 65.1, 45.2. IR (film): 1723 cm-1. HRMS (EI) m/z, calcd 140.0473,
found 140.0469. No precautions were taken to remove air. During the
reaction, a slight positive pressure develops due to the coproduction of
O2 gas; on a larger scale, this should be vented from the reactor.
(13) This observation indicate that Pd(OH)2-on-carbon is probably converted
to a species such as Pd(OH)(OOt-Bu)-on-carbon, which is an active
initiator of the oxidation of the R,â-enone. If Pd(OH)2-on-carbon is
prereduced to Pd(0)-on-carbon by stirring with hydrogen, it does not serve
as an effective reaction catalyst, although it is gradually oxidized by
t-BuOOH to a form that shows some catalytic activity.
Scheme 1
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species is unclear, the postulate shown in Scheme 1 requires its
reoxidation to Pd(II) by t-BuOOH. The final step of the process
outlined in Scheme 1 is the carbonyl-forming elimination of a
peroxy ether catalyzed either by base or by the tert-butylperoxy
radical.20 The conversions 5 f 6 and 8 f 9 support the
intermediacy of a γ-tert-butylperoxy-R,â-enone as shown in Scheme
1. In the case of the oxidation of 5, some radical trapping by O2
must occur leading to the sequential formation of 7b and 7a. Finally,
the formation of t-BuOH as a coproduct of these oxidations was
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