Regioselective Wacker-Type Oxidation of Internal Olefins in tBuOH Using Oxygen as the Sole Oxidant and tBuONO as the Organic Redox Cocatalyst

Article abstract of DOI:10.1021/acs.orglett.9b04503

A regioselective Wacker-Tsuji oxidation of internal olefins in ^tBuOH has been developed using oxygen as the terminal oxidant and tert-butyl nitrite as the simple organic redox cocatalyst without the involvement of hazardous cocatalysts or harsh reaction conditions. A series of internal olefins bearing various functional groups can be oxidized to the corresponding substituted ketones in generally good yields with high regioselectivities.

Full text of DOI:10.1021/acs.orglett.9b04503

pubs.acs.org/OrgLett
Letter
t
Regioselective Wacker-Type Oxidation of Internal Olefins in BuOH
t
Using Oxygen as the Sole Oxidant and BuONO as the Organic
Redox Cocatalyst
Qing Huang, Ya-Wei Li, Xiao-Shan Ning, Guo-Qing Jiang, Xiao-Wei Zhang, Jian-Ping Qu,*
and Yan-Biao Kang*
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ABSTRACT: A regioselective Wacker−Tsuji oxidation of internal olefins in
tBuOH has been developed using oxygen as the terminal oxidant and tert-butyl
nitrite as the simple organic redox cocatalyst without the involvement of hazardous
cocatalysts or harsh reaction conditions. A series of internal olefins bearing various
functional groups can be oxidized to the corresponding substituted ketones in
generally good yields with high regioselectivities.
he industrial oxidation process for converting ethylene to
co-workers have developed an aldehyde-selective Wacker−
Tacetaldehyde by means of palladium catalyst is known as Tsuji oxidation of terminal olefins, in which one example of
allylic internal olefin oxidation was included.4c Sigman and co-
workers have developed a catalytic system for the Wacker
oxidation, in which tert-butylhydroperoxide (TBHP) was used
as an alternative for the copper salts,5 in which two examples
using trans-β-methylstyrene or trans-stilbene were investigated.
In both cases, a low yield as a result of oxidative cleavage of the
internal olefins and low regioselectivity were observed. Kaneda
and co-workers reported a copper-free Wacker-type oxidation
of internal olefins using PdCl2 in the presence of N,N-
dimethylacetamide and high oxygen pressures (3−8 atm).6
Grubbs and co-workers reported an oxidation of internal
olefins using Pd(OAc)2 in a mixture of DMA, MeCN, and
H2O, and dilute acid is also necessary in this reaction system.7
Considering the facts that the simple internal olefins are
easily available from the petrochemical industry and that
substituted ketones are the important organic intermediate, the
development of a simple, selective, and practical Wacker-type
aerobic oxidation of internal alkenes without hazardous
cocatalysts or harsh conditions is therefore highly desirable.
We have developed an aldehyde-selective aerobic Wacker−
Tsuji oxidation using oxygen as the sole oxidant using tert-
butyl nitrite as a simple organic redox cocatalyst.8 No
hazardous cocatalysts or harsh conditions are required. We
found the solvent is crucial to the regioselectivity. Switching
the solvent could realize the regioselectivity (ketone/aldehyde
selectivity) control.9 During our further investigations, we
the Wacker process.1 It proceeds under aerobic conditions, and
copper salts are usually used as transition metal redox
cocatalysts. A wide variety of terminal olefins could be
selectively oxidized to the corresponding methyl ketones
using Wacker-type oxidation following the Markovnikov rule.2
However, Wacker-type aerobic oxidation of internal olefins has
been less studied, because it normally proceeds with low
activity or with low regioselectivity. Besides, the involvement of
a toxic transition metal reagent or hash condition is required.3
For example, Tsuji,4a Keinan,4b et al. have reported the
catalytic Wacker-type oxidation of substituted allylic ethers and
ester but with relatively low yields (Scheme 1a). Feringa and
Scheme 1. Wacker Oxidation of Internal Olefins Using
Oxygen as Terminal Oxidant
Received: December 16, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04503
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Table 1. Wacker Oxidation of Internal Olefins Using Oxygen as the Terminal Oxidant
a
Standard conditions: 1 (0.5 mmol), Pd(PhCN)2Cl2 (0.0375 mmol, 7.5 mol %), tBuONO (0.1 mmol, 20 mol %), oxygen (1 atm), and tBuOH (2
b
c
d
e
mL), rt. Isolated yield. Ratio of 2/3 is determined by 1H NMR analysis of crude products. Reaction was performed in 1 mmol scale. Isolated
yield for a mixture of 2 and 3; for details, see experimental details in Supporting Information. MeOH was used instead of BuOH.
f
t
found that using the same reaction conditions, the internal
olefins could be oxidized with good yields and high
regioselectivity without hazardous cocatalysts or harsh reaction
conditions (Scheme 1b). Herein we present our recent results
in detail.
The optimal reaction conditions were established to evaluate
the scope of internal olefins bearing a variety of functional
groups by using 7.5 mol % of Pd(PhCN)2Cl2, 20 mol %
tBuONO, and 1 atm of oxygen in the presence of 2 mL of
tBuOH after screening the reaction conditions (Table 1). Both
alkyl and aryl substituted internal olefins 1a−1l could be
converted to the corresponding substituted ketones 2a−2l
with good yield and high regioselectivity. Aliphatic (E)-allylic
ethers 1a and bulky alkyl-substituted (E)-allylic ethers 1b
could undergo regioselective Wacker−Tusji oxidation
smoothly providing the corresponding ketones 2a−2b in
excellent yields with a regioselectivity of more than 20:1
(entries 1−2). Aliphatic (E)-allylic amides 1c−d could also be
converted to the corresponding methyl ketones 2c−d
efficiently with the regioselectivity of more than 10:1 (entries
3−4). When aliphatic (E)-homoallylic ester 1e was subjected
to the standard reaction conditions, substituted methyl ketone
2e was obtained in 79% yield with a regioselectivity of 6:1.
Using MeOH instead of tBuOH did not improve the
B
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regioselectivity and gave a lower yield (entry 5). On the other
hand, (Z)-allylic ethers 1f and (Z)-homoallylic ester 1g could
also be oxidized using the standard conditions to give the
corresponding ketone 2f and 2g in 81% and 79% yields with
>20:1 and 5:1 regioselectivities, respectively (entries 6−7).
Aromatic (E)-allylic esters with an electron-donating group on
the benzoyl group 1h displays a relatively low yield (entry 8),
while aromatic (E)-allylic esters with an electron-withdrawing
group on the benzoyl group 1i and cinnamyl benzoate 1j
reacted smoothly under the standard reaction conditions
affording 2i and 2j in 84% and 75% yield, respectively (entries
9−10). Cinnamyl acetate 1k was also subject to the standard
conditions, and the corresponding oxidation product 2k could
be obtained in 68% yield with 10:1 regioselectivity (entry 11).
Aromatic (E)-allylic carbonate 1l was also tolerant of the
standard reaction conditions generating 2l in 83% yield with
>20:1 regioselectivity (entry 12).
Table 2. Wacker Oxidation of Internal Olefins Using
Oxygen as the Terminal Oxidant
a
Oxidation of internal olefins without weak coordinating
groups has also been investigated, and the results are
summarized in Table 2. Cyclohexene 1m and cyclopentene
1n afforded the oxygenation products 2m−n in moderate
yields (entries 1−2). Oxidation of linear internal olefins
required increased amounts of catalyst loading and prolonged
reaction times affording good yields albeit with relatively low
regioselectivities. Oxidation of trans-2-octene 1o provided 2-
octanone (2o), 3-octanone (2p), and 4-octanone (2q) in 54%,
28%, and 12% yield, respectively (entry 3). Oxidation of trans-
3-octene 1p afforded a mixture of 2o, 2p, and 2q in 88% yield
with a ratio of nearly 1:1:1 (entry 4). trans- (1q) and cis- (1r)
4-Octene were also subjected to the above-mentioned
oxidation conditions, and both produced a mixture of 2o,
2p, and 2q in good yields (entries 5−6). Oxidation of 1-
methylcyclohex-1-ene (1s) was also investigated affording the
corresponding oxidation product 2r in 16% yield (entry 7).
To demonstrate the synthetic utility of this aerobic oxidation
of internal olefins, cholesterol analogues (1t−1u) as well as a
derivative (1v) were prepared and subjected to the standard
reaction conditions for 20−24 h. The corresponding oxidation
products (2s−2u) were obtained in excellent yields with >20:1
regioselectivities (Table 3). These examples indicate that this
protocol could be used as a synthetically practical method for
the construction of ketone moieties from internal olefins.
t
To explore the role of BuONO, control experiments were
performed using 2,4,6-tri-tert-butylphenol 5 as a radical
scavenger. Oxidation of 1a was inhibited affording 2a in 4%
yield together with the isolation of a 5-NO adduct in 41% yield
calculated according to tBuONO (Scheme 2, eq 1). Moreover,
the reaction of 1a under standard conditions for 12 h afforded
t
2a in 55% yield. Using 5-NO instead of BuONO under the
same conditions afforded 2a in 63% yield (eq 2). These results
t
indicate BuONO plays the role of redox cocatalyst that
releases nitric oxide (NO), a stable neutral radical that is easily
oxidized to NO2 by O2.
Oxidation of (E)-homoallylic ester 1e under standard
reaction conditions produced 2e in 79% yield with a
regioselectivity of 2e/3e of 6:1. However, the regioselectivity
of 2e/3e dropped to 5:1 when 20 equiv of water were added
(Scheme 3, eq 3). This demonstrates that the solvent (tBuOH)
might be involved in the regioselectivity determining step.
Oxygen in the oxidation product could come from solvent
and/or oxygen. To verify the source of oxygen in the product
and to gain insight into the mechanism of this oxygenation, a
control experiment using H218O instead of water (H216O) was
a
Standard reaction conditions: 1 (0.5 mmol), Pd(PhCN)2Cl2 (0.0375
mmol, 7.5 mol %), tBuONO (0.1 mmol, 20 mol %), oxygen (1 atm),
and BuOH (2 mL), rt. Isolated yield. Reaction conditions: 1 (0.5
b
c
t
t
mmol), Pd(PhCN)2Cl2 (0.075 mmol, 15 mol %), BuONO (0.2
mmol, 40 mol %), oxygen (1 atm), and tBuOH (2 mL), rt. Yield and
regioselectivities of 2 were determined by GC analysis of the crude
products.
C
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a
Table 3. Wacker Oxidation of Internal Olefins Using Oxygen as the Terminal Oxidant
a
Reaction conditions: 1 (0.5 mmol), Pd(PhCN)2Cl2 (0.0375 mmol, 7.5 mol %), tBuONO (0.1 mmol, 20 mol %), oxygen (1 atm), and tBuOH (1
b
c
d
mL),CH2Cl2 (1 mL), rt. Pd(PhCN)2Cl2 (0.075 mmol, 15 mol %) Isolated yield. Ratio of 2/3 (distal oxidation/proximal oxidation) is
determined by H NMR analysis of crude products.
1
[(2e+3e)-18O] were detected by HRMS analysis of the final
Scheme 2. Control Experiments
products. This observation is compatible with our previously
proposed mechanism8,9 in which the oxygen in the product
may come from the solvents.
A plausible mechanism for regioselective Wacker−Tsuji
oxidation of internal olefins is proposed (Scheme 4). Pd(II)
coordinates with internal olefin 1 forming intermediate A.
t
Intermediate A is then attacked by the BuOH from the site
with less steric hindrance to generate intermediate B. The β-
elimination affords enol ether D as the main intermediate.
Scheme 4. Proposed Mechanism
a
Scheme 3. Control Experiments
a
Reaction conditions: 1e (0.5 mmol), Pd(PhCN)2Cl2 (0.0375 mmol,
t
7.5 mol %), BuONO (0.1 mmol, 20 mol %), oxygen (1 atm), and
tBuOH (2 mL), rt.
carried out under the developed conditions (eq 4). A
dramatically increased amount of 18O-labeled compounds
D
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Platinmetall-Verbindungen Das Consortium-Verfahren zur Herstel-
lung von Acetaldehyd. Angew. Chem. 1959, 71, 176−182. (b) Tsuji, J.
Synthetic Applications of the Palladium-Catalyzed Oxidation of
Olefins to Ketones. Synthesis 1984, 1984, 369−384.
Hydrolysis of enol ether with water promoted by HCl affords
ketone 2. The catalytically active Pd(II) species is then
regenerated by the oxidation of NO2 which is in situ generated
t
from the oxidation of NO with molecular oxygen. BuONO is
(2) Siegel, H. M. Eggersdorfer, Ullmann’s Encyclopedia of Industrial
Chemistry, Vol. 18, 6th ed.; Bohnet, M., Eds.; VCH: Weinheim, 2003;
p 739.
the donor of NO, and NO plays the role of redox cocatalyst.
In conclusion, we have developed a regioselective Wacker-
type oxidation of internal olefins without the involvement of
hazardous cocatalysts or harsh conditions. A catalytic amount
of tert-butyl nitrite worked as a simple organic redox cocatalyst.
A variety of ketones were prepared with generally high
regioselectivity in good to high yields.
(3) (a) Kou, X.; Li, Y.; Wu, L.; Zhang, X.; Yang, G.; Zhang, W.
Palladium-Catalyzed Aerobic Aminooxygenation of Alkenes for
Preparation of Isoindolinones. Org. Lett. 2015, 17, 5566−5569.
(b) Michel, B. W.; Camelio, A. M.; Cornell, C. N.; Sigman, M. S. A
General and Efficient Catalyst System for a Wacker-Type Oxidation
Using TBHP as the Terminal Oxidant: Application to Classically
Challenging Substrates. J. Am. Chem. Soc. 2009, 131, 6076−6077.
(c) Michel, B. W.; McCombs, J. R.; Winkler, A.; Sigman, M. S.
Catalyst-Controlled Wacker-Type Oxidation of Protected Allylic
Amines. Angew. Chem., Int. Ed. 2010, 49, 7312−7315. (d) DeLuca,
R. J.; Edwards, J. L.; Steffens, L. D.; Michel, B. W.; Qiao, X.; Zhu, C.;
Cook, S. P.; Sigman, M. S. Wacker-Type Oxidation of Internal
Alkenes using Pd(Quinox) and TBHP. J. Org. Chem. 2013, 78, 1682−
1686.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04503.
Experimental procedures, full analysis data for com-
pounds, and copies of NMR spectra (PDF)
(4) (a) Tsuji, J.; Nagashima, H.; Hori, K. Regioselective Oxidation
of Internal Olefins bearing Neighboring Oxygen Functions by means
of Palladium Catalysts. Preparation of β-Alkoxy or Acetoxy Ketones
from Allyl and Homoallyl Ethers or Esters. Tetrahedron Lett. 1982, 23,
2679−2682. (b) Keinan, E.; Seth, R. R.; Lamed, R. Organic Synthesis
with Enzymes. 3.1 TBADH-Catalyzed Reduction of Chloro Ketones.
Total Synthesis of (+)-(S′,5)-(c/j-6-Methyltetrahydropyran-2-yl)-
acetic Acid: A Civet Constituent. J. Am. Chem. Soc. 1986, 108,
3474−3480. (c) Weiner, B.; Baeza, A.; Jerphagnon, T.; Feringa, B. L.
Aldehyde Selective Wacker Oxidations of Phthalimide Protected
Allylic Amines: A New Catalytic Route to β3-Amino Acids. J. Am.
Chem. Soc. 2009, 131, 9473−9474.
AUTHOR INFORMATION
Corresponding Authors
■
Jian-Ping Qu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; orcid.org/0000-0002-5002-5594;
Email: ias_jpqu@njtech.edu.cn
Yan-Biao Kang − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China;
orcid.org/0000-0002-7537-4627; Email: ybkang@
ustc.edu.cn
(5) Cornell, C. N.; Sigman, M. S. Discovery of and Mechanistic
Insight into a Ligand-Modulated Palladium-Catalyzed Wacker
Oxidation of Styrenes Using TBHP. J. Am. Chem. Soc. 2005, 127,
2796−2797.
Authors
Qing Huang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Ya-Wei Li − Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University, Nanjing
211816, China
Xiao-Shan Ning − Department of Chemistry, University of
Science and Technology of China, Hefei 230026, China
Guo-Qing Jiang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Xiao-Wei Zhang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
(6) Mitsudome, T.; Mizumoto, K.; Mizugaki, T.; Jitsukawa, K.;
Kaneda, K. Wacker-Type Oxidation of Internal Olefins Using a
PdCl2/N,N-Dimethylacetamide Catalyst System under Copper-Free
Reaction Conditions. Angew. Chem., Int. Ed. 2010, 49, 1238−1240.
(b) Mitsudome, T.; Yoshida, S.; Mizugaki, T.; Jitsukawa, K.; Kaneda,
K. Highly Atom-efficient Oxidation of Electron-deficient Internal
Olefins to Ketones using a Palladium Catalyst. Angew. Chem., Int. Ed.
2013, 52, 5961−5964. (c) Mitsudome, T.; Yoshida, S.; Tsubomoto,
Y.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Simple and Clean
Synthesis of Ketones from Internal Olefins using PdCl2/N,N-
dimethylacetamide Catalyst System. Tetrahedron Lett. 2013, 54,
1596−1598.
(7) Morandi, B.; Wickens, Z. K.; Grubbs, R. H. Practical and
General Palladium-catalyzed Synthesis of Ketones from Internal
Olefins. Angew. Chem., Int. Ed. 2013, 52, 2944−2948.
(8) Ning, X.-S.; Wang, M.-M.; Yao, C.-Z.; Chen, X.-M.; Kang, Y.-B.
tert-Butyl Nitrite: Organic Redox Cocatalyst for Aerobic Aldehyde-
Selective Wacker-Tsuji Oxidation. Org. Lett. 2016, 18, 2700−2703.
(9) Hu, K.-F.; Ning, X.-S.; Qu, J.-P.; Kang, Y.-B. Tuning
Regioselectivity of Wacker Oxidation in One Catalytic System:
Small Change Makes Big Step. J. Org. Chem. 2018, 83, 11327−11332.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04503
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21602001, 21922109, 21672196, 21831007), the Start-up
Funding from Nanjing Tech University (39837134), and the
Fundamental Research Funds for the Central Universities of
China (WK2060190086) for financial support.
REFERENCES
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(1) (a) Smidt, J.; Hafner, W.; Jira, R.; Sedlmeier, J.; Sieber, R.; Kojer,
H.; Ruettinger, R. Katalytische Umsetzungen von Olefinen an
E
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