Tsuji-Wacker-Type Oxidation beyond Methyl Ketones: Reacting Unprotected Carbohydrate-Based Terminal Olefins through the "uemura System" to Hemiketals and α,β-Unsaturated Diketones

Article abstract of DOI:10.1021/acs.orglett.9b02134

Aerobic Pd(AcO)₂/pyridine-catalyzed oxidation of unprotected carbohydrate-based terminal alkenes was studied. In accordance with previous reports, the initial reaction step gave methyl ketones. However, our substrates partially gave subsequent α,β-water elimination and alcohol oxidation to α,β-unsaturated 2,5-diketones. Upon increasing the pressure of O₂, the reaction was shifted toward formation of α,β-epoxy-2-ketones. The reactions were stereoselective and gave up to quantitative conversions. However, isolated yields were substantially lower because of the complexity of the product mixtures.

Full text of DOI:10.1021/acs.orglett.9b02134

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tsuji−Wacker-Type Oxidation beyond Methyl Ketones: Reacting
Unprotected Carbohydrate-Based Terminal Olefins through the
“Uemura System” to Hemiketals and α,β-Unsaturated Diketones
Patrik A. Runeberg* and Patrik C. Eklund*
Laboratory of Organic Chemistry, Johan Gadolin Process Chemistry Centre, Åbo Akademi University, Piispankatu 8, 20500 Turku,
Finland
S
* Supporting Information
ABSTRACT: Aerobic Pd(AcO)2/pyridine-catalyzed oxidation of unprotected carbohydrate-based terminal alkenes was
studied. In accordance with previous reports, the initial reaction step gave methyl ketones. However, our substrates partially
gave subsequent α,β-water elimination and alcohol oxidation to α,β-unsaturated 2,5-diketones. Upon increasing the pressure of
O2, the reaction was shifted toward formation of α,β-epoxy-2-ketones. The reactions were stereoselective and gave up to
quantitative conversions. However, isolated yields were substantially lower because of the complexity of the product mixtures.
Scheme 1. Uemura System for Aerobic Wacker-Type
Oxidation of Terminal Olefins
he Tsuji−Wacker oxidation, a lab-scale version of the
TWacker oxidation, is a palladium(II)-catalyzed oxidation
reaction for conversion of alkenes to ketones and aldehydes.1,2
It is an important reaction which has extensive applications in
both the laboratory and industry.3,4 The method originally
used PdCl2 in combination with CuCl2 in an oxygen
atmosphere, but has later included also other Pd-species,
such as Pd(OAc)2. The mechanism and kinetics of the catalytic
cycle has been extensively studied and reviewed.5−8
A system for oxidation of alkenes to carbonyls by
palladium(II) in the presence of H2O2 was reported in
1980.9 The proposed catalytic cycle formed Pd(II)OOH as the
active species, which was regenerated by H2O2 (cycle B in
Scheme 1). In a different context in 1998, Uemura et al.
reported a novel aerobic Pd(OAc)2-pyridine system for
oxidation of alcohols to carbonyls and generating H2O2.10,11
The system used 2-propanol (IPA) for generating H2O2,
releasing acetone as a side product (cycle A in Scheme 1).
Furthermore, Pd(II)OOH was formed as a catalyst-species in
the catalytic cycle. Thus, by adding an olefin to the reaction,
Uemura et al. combined cycle A and cycle B for oxidation of
olefins to carbonyls, as seen in Scheme 1.12 The proposed
mechanism of cycle A is based on studies reported by Stahl and
Popp.13
unsaturation, was shown to be acid promoted in cases where
the initially formed methyl ketone product had a β-hydroxyl
group. Aliphatic methyl ketone products, on the other hand,
Previously, Wacker-type palladium(II)-catalyzed oxidations
of terminal olefins to α,β-unsaturated methyl ketones have also
been reported. There, the elimination step, giving the α,β-
Received: June 20, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02134
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
were suggested to form α,β-double bonds through catalytic α-
hydride elimination.14−16 Here, we report the formation of
α,β-unsaturated 2,5-diketones from carbohydrate-based poly-
olic terminal olefins. To the best of our knowledge, no Wacker-
type oxidations to these types of substrates have previously
been reported.
However, the reaction had a lower observed conversion of
around 80%.
When the pressure of the oxygen atmosphere was increased
to 2 bar, the reaction resulted in a quantitative conversion
(observed by GC-MS and NMR) to three major products in a
15:7:3 ratio. The major product was 5 here also. However, the
other products were epoxyderivatives of five- and six-
membered rings (7a and 7b) which were in equilibrium in a
3:7 ratio (Scheme 2, path B). Additionally, traces of
degradation products were observed.
The substrates 1−3 (Figure 1) were prepared at our
laboratory according to literature procedures through metal-
Higher pressure of O2 only decreased the reaction
selectivity. When reacted at 3 and 6 bar, the same products
were formed as at 2 bar (5, 7a, and 7b) in a similar 15:7:3
ratio. However, in these cases broader mixtures of byproducts
were seen in NMR analysis.
Also, when the solvent was changed to toluene, no reaction
occurred (2 bar O2). This clearly indicates that isopropanol is
needed to initiate the catalytic cycles.
Figure 1. Substrate scope of allylated polyols.
A proposed mechanism for the formation of products is
presented in Scheme 3. The first step is the Tsuji−Wacker
oxidation of the terminal alkene to the corresponding methyl
ketone (8). The methyl ketone was partially ring closed to
hemiketal 5. Compound 8 also partially formed an enone
intermediate (E- and Z-9) through α,β-elimination of water. In
1 bar oxygen, this intermediate may function as the substrate in
the catalytic cycle A (seen in Scheme 1 for 2-propanol),
forming an α,β-unsaturated diketone (10) which further ring
closed to 6. Palladium-catalyzed E-Z-isomerization of 9
combined with coordination to the adjacent carbonyl
presumably locked 9 in Z-configuration during oxidation to
10, and no E-isomer of 10 was observed.
mediated allylation of unprotected monosaccharides.17−19
Allylated D-mannose (1) was retrieved as pure threo-isomer
through recrystallization in ethanol, while substrates 2 and 3
were used as stereoisomeric mixtures. 4-Penten-2-ol (4) was
purchased from a commercial source as a racemic mixture.
Substrate 4 was used in this study because of the simplicity of
the structure.
We started our investigation using 1 as substrate in the
“Uemura system”. The oxidation reaction in 1 bar molecular
oxygen atmosphere for 20 h at 60 °C resulted in a quantitative
conversion (observed by GC-MS and NMR) to two major
products in a 3:2 ratio (Scheme 2, path A). The major product
At 2 bar oxygen atmosphere, epoxidation of 8 occurred,
forming an epoxy-ketone (11) which further ring closed in
equilibrium to products 7a and 7b. A logical explanation for
the epoxide formation would be a nucleophilic attack, by H2O2
or other hydrogen peroxy species, on enone intermediate 9.
However, this mechanism is unlikely as the absolute
configuration at the β-hydroxyl in 1 (S) remained in the
formed epoxide. For further proof, the erythro-isomer of 1, (R-
conformation at β-position), gave an epoxide with the
corresponding stereochemistry. (See the Supporting Informa-
tion for more details.)
Scheme 2. Aerobic Palladium-Catalyzed Oxidation of 1 in a
1 or 2 bar Molecular Oxygen Atmosphere
Previously, intramolecular Wacker cyclizations of alkene-ols
have been reported under similar reaction conditions, forming
ethers through nucleophilic attack by alcohols to C−C double
bonds.20 Although a similar pathway may have occurred at the
double bond of a palladium-stabilized enolate-intermediate, to
the best of our knowledge, no such mechanisms have
previously been reported on enols. Therefore, a thorough
mechanistic study is needed to fully understand the α-
epoxidation step.
The reactions with 2−4 gave lower conversions compared to
allylated D-mannose (Table 1). Also more byproducts were
observed compared to 1. This may be due to the racemic
mixtures of 2−4. Moreover, no other substrate formed the
corresponding epoxides, even when the pressure of oxygen was
increase to 2 bar. At this pressure 2−4 formed the same
products as at 1 bar, only with higher reaction conversions.
The reaction of 3 distinguished from the others as the
second major product (14) was formed through double water
elimination of product 13.
(5) was a hemiketal, and the other was a tetrahydrofuran-
dihydrofuran bicyclic spiroketal (6). Both products were
identified as single stereoisomers. When the reaction was
performed in open air, instead of an atmosphere of molecular
oxygen, the same products were again formed in a 3:2 ratio.
Substrate 4 gave the corresponding methyl ketone 15 as
major product together with product 16, which was formed
B
DOI: 10.1021/acs.orglett.9b02134
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Scheme 3. Proposed Reaction Pathways for the Formation of Products
a
Table 1. Observed Conversions and Products after Oxidation at 1 and 2 bar Molecular Oxygen
a
iy, isolated yield after column chromatography of the crude reaction mixture. Where no isolated yield is given, the products were analyzed in a
b
reaction mixture without further isolation. Product 12 could not be separated from product 6 and other byproducts by column chromatography.
Also it was partially reacted to new mixtures of byproducts in the column.
C
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(2) Tsuji, J.; Nagashima, H.; Nemoto, H. A General Synthetic
Method for the Preparation of Methyl Ketones from Terminal
Olefins: 2-Decanone. Org. Synth. 1984, 62, 9−13.
through olefin migration. Only traces (<1%) of the
corresponding olefin-ketone (3-penten-2-one) was detected.
As an observation, all ring-closed products (hemi- and
spiroketals) were identified through NMR analyses in D2O.
We cannot exclude that the ring closing take place in the NMR
samples because of the aqueous environment.
For isolation and unambiguous identification of the
products, the reaction mixtures were purified through column
chromatography using an ethyl acetate and methanol eluent
system. Because of the complexity of the products and the
equilibrium between different forms, the isolation and
identification were difficult, and the isolated yields were
substantially lower than the conversions. This was especially
challenging for the isomers of product 12, and only traces
could be isolated.
For better separation, the reaction mixtures were also
subjected to acetylation reactions prior to column chromatog-
raphy. During the acetylations, all ring-closed products, aside
from 6, were opened and acetylated as the corresponding
open-chain ketones. Products 7a and 7b gave a single open-
chain epoxyketone. Products 5 and 12 underwent water
elimination to α-unsaturated methyl ketones. The isolated
yields were increased for all products, but because of water
elimination, products 5 and 12 could not be retrieved through
deacetylation of the isolated products. (See the Supporting
Information for more details.)
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02134.
Additional results, discussion, experimental procedures,
characterization data, and NMR spectra for all novel
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: patrik.runeberg@abo.fi.
*E-mail: paeklund@abo.fi.
ORCID
(16) Bigi, M. A.; White, M. C. Terminal Olefins to Linear α,β-
Unsaturated Ketones: Pd(II)/Hypervalent Iodine Co-Catalyzed
Wacker Oxidation-Dehydrogenation. J. Am. Chem. Soc. 2013, 135
(21), 7831−7834.
Patrik A. Runeberg: 0000-0002-5636-2786
Patrik C. Eklund: 0000-0003-3040-5116
Notes
(17) Kim, E.; Gordon, D. M.; Schmid, W.; Whitesides, G. M. Tin-
and Indium-Mediated Allylation in Aqueous Media: Application to
Unprotected Carbohydrates. J. Org. Chem. 1993, 58 (20), 5500−
5507.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(18) Saloranta, T.; Muller, C.; Vogt, D.; Leino, R. Converting
̈
This research work was funded by Academy of Finland Project
No. 265726. Also, The Swedish Cultural Foundation in
Finland (Svenska kulturfonden) is thanked for their financial
support (Grant No. 136293). Ida Mattson at the Laboratory of
Organic Chemistry at Åbo Akademi University is thanked for
the synthesis and recrystallization of substrate 1. Matilda
Unprotected Monosaccharides into Functionalised Lactols in
Aqueous Media: Metal-Mediated Allylation Combined with Tandem
Hydroformylation-Cyclisation. Chem. - Eur. J. 2008, 14 (34), 10539−
10542.
(19) Saloranta, T.; Peuronen, A.; Dieterich, J. M.; Ruokolainen, J.;
Lahtinen, M.; Leino, R. From Mannose to Small Amphiphilic Polyol:
Perfect Linearity Leads To Spontaneous Aggregation. Cryst. Growth
Des. 2016, 16 (2), 655−661.
̈
Kråkstrom at the Laboratory of Organic Chemistry at Åbo
Akademi is thanked for the HRMS results.
́
̌
̌
́
(20) Dohanosova, J.; Gracza, T. Asymmetric Palladium-Catalysed
Intramolecular Wacker-Type Cyclisations of Unsaturated Alcohols
and Amino Alcohols. Molecules 2013, 18 (6), 6173−6192.
REFERENCES
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(1) Tsuji, J. Synthetic Applications of the Palladium-Catalyzed
Oxidation of Olefins to Ketones. Synthesis 1984, 5, 369−384.
D
DOI: 10.1021/acs.orglett.9b02134
Org. Lett. XXXX, XXX, XXX−XXX