Synthesis of α,β-unsaturated carbonyl compounds via a visible-light-promoted organocatalytic aerobic oxidation

Article abstract of DOI:10.1039/c3cc46778c

α,β-Unsaturated ketones and aldehydes have been synthesized from their corresponding silyl enol ethers in a straightforward protocol involving a visible-light promoted organocatalytic, aerobic oxidation reaction. A cheap organic dye was used catalytically in these reactions as the photosensitizer.

Full text of DOI:10.1039/c3cc46778c

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Synthesis of a,b-unsaturated carbonyl compounds
via a visible-light-promoted organocatalytic
aerobic oxidation†
Cite this: DOI: 10.1039/c3cc46778c
Received 5th September 2013,
Accepted 18th October 2013
Junlin Zhang,a Leming Wang,a Qi Liu,a Zhen Yang*ab and Yong Huang*a
DOI: 10.1039/c3cc46778c
www.rsc.org/chemcomm
a,b-Unsaturated ketones and aldehydes have been synthesized
from their corresponding silyl enol ethers in a straightforward
protocol involving a visible-light promoted organocatalytic, aerobic
oxidation reaction. A cheap organic dye was used catalytically in
these reactions as the photosensitizer.
Scheme 1 Representative strategies for the oxidation of carbonyl compounds
to their corresponding a,b-unsaturated derivatives.
a,b-Unsaturated carbonyl subunits are important structural motifs
and arguably one of the most versatile synthetic intermediates for
the construction of structurally diverse natural products, as well as a photocatalytic, aerobic system for the synthesis of a,b-unsaturated
variety of other functional molecules.1 Compounds containing these aldehydes and ketones from structurally diverse silyl enol ethers.
structural units can participate in a large number of highly privileged
We initially attempted to use the oxidation of a cyclohexanone-
organic transformations, which lead to formation of products of derived TBS enol ether 1a as a model reaction using a variety of
pronounced structural diversity. Several representative approaches different photosensitizers and O2 under different visible light
using some of the more readily available saturated carbonyl feed- sources. All of these reactions were carried out at room tempera-
stock have been reported in the literature. For example, Nicolaou ture in DMF (Table 1). The desired cyclohexenone product 2a was
et al.2 developed a convenient method for the oxidation of ketones observed when Ru(bpy)3Cl2 (5 mol%) was used as a metallic
and aldehydes to their a,b-unsaturated derivatives using stoichio- sensitizer under several household light sources.
metric IBX. More recently, Stahl et al.3 as well as our own group4
Energy-saving compact fluorescent light bulbs (Philips,
reported the direct aerobic catalytic dehydrogenation of aldehydes Tornado-24 W) were found to be the most efficient of the house-
and ketones via a palladium enolate intermediate. In practice, hold light sources for promoting the desired oxidation, affording
the Saegusa–Ito oxidation is frequently used as an effective the desired product 2a in 41% yield after 15 hours (Table 1, entry 3).
method for the introduction of a CQC double bond next to an We then proceeded to investigate the effect of several organic dyes.
aldehyde or a ketone, especially in the context of natural product While rhodamine B and alizarin failed to catalyze this oxidation
synthesis (Scheme 1).5,6
(Table 1, entries 4 and 5), TPP and Eosins B and Y were found to be
The benefit of using silyl enol ethers is that they enable quite effective (Table 1, entries 6–8). In the absence of a photo-
convenient control of the regiochemical outcome of the reaction.7 catalyst or light, no enone product was observed. In addition, when
The Saegusa reaction requires palladium as the catalyst to mediate the reaction was conducted in a glovebox, no reaction occurred.
the oxidation in the presence of an external oxidant.8 Metal-free
We then proceeded to investigate the effect of solvents on
protocols using molecular oxygen as the sole oxidant remain this aerobic oxidation reaction (Table 2). In most of the non-
scarce. Herein we report for the first time a transition-metal-free, polar and polar aprotic solvents tested, except for DMSO, low
conversions of the starting material were observed, with the
saturated ketones being isolated as the major side-product. In
contrast, the use of polar protic solvents, such as methanol and
ethanol, as well as the polar aprotic solvent DMSO, led to
reasonable yields of the desired cyclohexenone products. The
major side reaction was the ozonolysis-like oxidative cleavage of
the enol ether double bond.
a Key Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University, Shenzhen Graduate School, Shenzhen,
518055, China
b Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
Minster of Education and Beijing National Laboratories for Molecular Science,
College of Chemistry, Peking University, Beijing 100871, China.
E-mail: zyang@pku.edu.cn, huangyong@pkusz.edu.cn
The reaction scope was then studied using different silyl
enol ethers, and the results are summarized in Table 3.
† Electronic supplementary information (ESI) available: Experimental procedures
and analytical data of the products. See DOI: 10.1039/c3cc46778c
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Table 1 Initial investigation of different light sources and photosensitizers for
the oxidation of 1aa
Table 3 Substrate scopea
Entry
Light source
Photocatalyst
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
LED corn light (12 W)
LED green light (9 W)
Fluorescent bulb (24 W)
Fluorescent bulb (24 W)
Fluorescent bulb (24 W)
Fluorescent bulb (24 W)
Fluorescent bulb (24 W)
Fluorescent bulb (24 W)
—
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Rhodamine B
Alizarin
TPP
Eosin B
Eosin Y
Eosin Y
—
9
13
41
0
0
32
33
45
0
Fluorescent bulb (24 W)
0
a
The reaction was carried out on a 1 mmol scale. Conditions: 1 (0.2 M);
b
1 atm O2; r.t.; 15 hours. Yields were determined by GC using biphenyl
as the internal standard.
a
Isolated yield.
Table 2 Solvent effects and the influence of additivesa
as well as theoretical calculations. We therefore attempted to trap
a similar oxygenated allylic radical using cyclopropane substituted
substrates (Scheme 2, eqn (1) and (2)).
To this end, silyl enol ethers 1o and 1p were prepared, and
oxidized under the optimized conditions. Interestingly, 2o and 2p
were formed as the cyclopropane substituted a,b-unsaturated
ketones, excluding that the TBSO-substituted allylic radicals were
intermediates for the reaction. An a-cyclopropyl silyl enol ether (as a
mixture of regioisomers: 1q and 1q0) was synthesized and subjected
to our standard conditions. The isolation of the cyclopropane bearing
products only strongly disfavoured an a-keto radical pathway
(Scheme 2).11 The rate of the photocatalytic aerobic oxidation reaction
Entry
Cat. (mol%)
Solvent
Additivea
Yieldb (%)
1
2
3
4
5
6
7
8
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
0.2
0.2
Toluene
THF
DCM
—
—
—
—
—
—
—
—
5
19
10
12
16
35
20
52
59
59
65
DME
Dioxane
CH3CN
Acetone
DMSO
MeOH
EtOH
9
—
—
AcOK
10
11c
EtOH
a
b
The reaction was carried out on a 1 mmol scale. Yields were
c
determined by GC using biphenyl as the internal standard. The
reaction was carried out for 4 hours at +4 1C; isolated yield.
The overall utility of our new protocol was then evaluated using
the structurally sophisticated intermediates 1m and 1n, which
have been used as building blocks in the total syntheses of
dysidavarones A–D and solanoeclepin A.9 Despite the multiple
functionalities present in these molecules, our oxidation reactions
proceeded smoothly to give enones 2m and 2n in good yields.
A TMS analogue of 1n showed similar reactivity, while the corre-
sponding TIPS substrate led to low conversion. A gram scale
reaction using 2k afforded a similar yield, while using 1.0 mol%
photosensitizer.
We then moved on to investigate the mechanism of this
transformation. MacMillan et al.10 recently reported a visible light
photoredox protocol for the functionalization of the b-carbon
atoms of saturated ketones and aldehydes. This particular reaction
was reported to proceed via a stabilized amino allyl radical inter-
mediate, which was supported by the experimental evidence,
Scheme 2 Radical clock and isotope experiments.
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This work was financially supported by grants from the National
973 Program (2012CB722602), and the Shenzhen Municipal govern-
ment (JC201104210112A and GJHZ201206-14144733420), and the
Shenzhen Peacock Program (KQTD201103).
Notes and references
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Comprehensive Organic Transformations, John Wiley & Sons, New York,
1999, p. 251.
Scheme 3 Proposed reaction mechanism.
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was zero order with respect to the catalyst and first order to the
substrate concentration (see the ESI† for detailed kinetic studies).
A reaction under an 18O2 balloon did not result in the incorporation
of any 18O in the product. Instead, TBS 18OH was detected as the
major silicon by-product by HRMS, with a negligible isotope effect
(K16O/18O = 1.05). No 18O was found within the catalyst framework.
A further experiment involving the use of a fully deuterated substrate
yielded an isotope effect of KH/D = 1.27, suggesting that the C–H bond
cleavage was not involved in the rate limiting step.
Based on the experimental data provided above and informa-
tion from the literature, we speculate a singlet oxygen mechanism
for this transformation. Eosins are known to excite molecular
oxygen from its triplet state to its singlet state under light
radiation.12 An ene reaction between the singlet oxygen and the
silyl enol ether through intermediate A (Scheme 3) to generate
a hydroperoxy silyl hemiacetal B has been reported.13 This inter-
mediate B might undergo an intramolecular silyl transfer to release
the desired product together with hydroperoxysilane, which would
decompose to form O2 and silanol. It is noteworthy that in contrast
to conventional photosensitized singlet oxygen protocols, which
require intense light sources (such as 300 W Hg lamps or photo-
reactors), the current oxidation reaction relies on simple exposure
to a household light source to initiate the oxidation, possibly
due to direct conversion of the hydroperoxysilane to singlet
oxygen catalyzed by Eosin Y*. An in-depth mechanistic study is
currently underway in our laboratories to fully elucidate the
mechanism of this reaction.
´
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of a,b-unsaturated ketones and aldehydes from their corresponding
silyl enol ethers in a straightforward manner involving a visible-light
organocatalytic, aerobic oxidation reaction. This protocol has several
practical advantages over the existing procedures for the synth-
esis of a,b-unsaturated carbonyl compounds: it is metal-free,
uses an inexpensive commercial catalyst, requires only ultralow
catalyst loading, operates under aerobic conditions, uses ethanol
as a low toxicity solvent, and operates effectively at ambient or
even lower temperatures.
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c
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