Aerobic Oxidative Dehydrogenation of Ketones to 1,4-Enediones

Article abstract of DOI:10.1021/acs.orglett.0c04174

An efficient and unprecedented strategy for the synthesis of 1,4-enediones from saturated ketones has been developed via palladium-catalyzed oxidative dehydrogenation. The protocol employs molecular oxygen as the sole oxidant and represents an atom- and step-economic process. The approach showed broad substrate scope, good functional group tolerance, and complete E-stereoselectivity. The reaction mechanism has been investigated through deuterium-labeling experiments and intermediate experiments.

Full text of DOI:10.1021/acs.orglett.0c04174

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Letter
Aerobic Oxidative Dehydrogenation of Ketones to 1,4-Enediones
Bao-Yin Zhao, Xing-Long Zhang, Rui-Li Guo, Meng-Yue Wang, Ya-Ru Gao, and Yong-Qiang Wang*
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ABSTRACT: An efficient and unprecedented strategy for the
synthesis of 1,4-enediones from saturated ketones has been
developed via palladium-catalyzed oxidative dehydrogenation. The
protocol employs molecular oxygen as the sole oxidant and
represents an atom- and step-economic process. The approach
showed broad substrate scope, good functional group tolerance, and
complete E-stereoselectivity. The reaction mechanism has been
investigated through deuterium-labeling experiments and intermedi-
ate experiments.
1,4-Enediones constitute a privileged structural motif of many
bioactive natural products and pharmaceuticals (Figure 1).1
Scheme 1. Oxidative Synthesis of 1,4-Enediones
Figure 1. Examples of natural products with 1,4-enediones.
1,4-Enediones also serve as versatile precursors in the
construction of various heterocycles such as furans, thiophenes,
pyrroles, pyrazines, and indolizines.2 In addition, by virtue of
their distinctive electrophilicity and electron affinity, they have
been used as highly reactive electrophiles and dienophiles to
construct complex molecules.3 Owing to their importance, the
synthetic methodologies of 1,4-enediones have attached
considerable attention, and remarkable progress has been
made over the past decades.4−9 Traditionally, 1,4-enediones
were synthesized by oxidative ring opening of furan and
thiophene derivatives,5 decomposition of α-diazo carbonyl
compounds,6 and Wittig reaction.7 In 2003, Yu and Corey
developed an oxidative protocol to synthesize 1,4-enediones
from α,β-enones utilizing a Pd(OH)2-on-C/K2CO3/t-BuOOH
system (Scheme 1a).10 Later, Doyle et al. reported a
dirhodium(II) caprolactamate catalyzed allylic oxidation
protocol that also enabled the preparation of 1,4-enediones
from α,β-enones (Scheme 1b).11 Compared to the traditional
methods, the oxidation dehydrogenative protocol of α,β-
enones is much more concise, efficient, and atom- and step-
economic.12 Herein, we reported the first direct aerobic
oxidative dehydrogenation of saturated ketones into 1,4-
enediones (Scheme 1c).
Ketone is very common, cheap, and readily accessible
substrate. Therefore, it would be a more valuable synthetic
route to construct 1,4-enedione directly from ketone.
However, the protocol is extremely challenging due to the
selective cleavage of four inert C−H bonds in one step. Our
study commenced with 1,4-diphenylbutan-1-one (1aa) as the
model substrate. We initially chose Pd(OAc)2 (10 mol %) as
the catalyst and trifluoroacetic acid (TFA, 5.0 equiv) as the
additive in DMSO at 80 °C for 48 h under O2. To our delight,
the desired product 1,4-enedione was obtained in 21% yield
and with complete E-stereoselectivity (Table 1, entry 1).
Received: December 16, 2020
Published: February 2, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04174
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1216−1221
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a
Supporting Information). Accordingly, the reaction conditions
were optimized as follows: Pd(OAc)2 (12.5 mol %), Cu(OAc)2
(30 mol %), and TFA (5.0 equiv) under an oxygen atmosphere
in DMSO at 80 °C.
Table 1. Optimization of Reaction Conditions
With the optimal conditions in hand, we first investigated
the effect of the substituents on the left aromatic ring (Scheme
2, 2aa−2at). Both electron-donating and electron-withdrawing
b
TFA
yield
entry
Pd source
Pd(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(TFA)2 Cu(OAc)2
PdCl2
Pd(PPh3)4 Cu(OAc)2
Pd(OH)2
Pd2(dba)3
-
additive
(equiv)
solvent
DMSO
(%)
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
21
61
58
17
47
57
59
NR
<20
a,b
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
other
Scheme 2. Substituents on the Left Aromatic Ring
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
c
9
Pd(OAc)2 Cu(OAc)2
solvents
10
Pd(OAc)2 Cu(OAc)2·
5.0
DMSO
52
H2O
11
12
13
14
Pd(OAc)2 Cu(OAc)
Pd(OAc)2 CuSO4
Pd(OAc)2 FeSO4
5.0
5.0
5.0
5.0
5.0
5.0
5.0
-
1.0
2.0
10.0
5.0
5.0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
57
51
50
16
8
<65
65
trace
15
53
64
Pd(OAc)2 AgOAc
d
15
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
Pd(OAc)2 Cu(OAc)2
e
16
f
17
f
18
f
19
f
20
f
21
f g
22 ,
82
83
a
f h
23 ,
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (12.5 mol %),
a
Cu(OAc)2 (30 mol %), and TFA (5.0 equiv) in DMSO (2 mL) at 80
°C for 48 h. Isolated yields.
Reaction conditions: 1aa (0.25 mmol), [Pd] (10 mol %), additive
b
b
c
(10 mol %), solvent (1 mL), 80 °C for 48 h. Isolated yield. Other
solvents: H2O, acetone, CH3CN, HOAc, EtOAc, DMF, formamide,
piperidine, 1,4-dioxane, toluene, xylene, benzene, MeOH, EtOH,
HFIP, CHCl3, THF. Without O2. Amount of Cu(OAc)2: 1 mol %
(48%), 5 mol % (54%), 50 mol % (64%), 1.0 equiv (59%), 2.0 equiv
groups were well tolerated, furnishing the desired products in
52−92% yields. Notably, the substrates bearing electron-
withdrawing groups (F, Cl, Br, CF3, CN) exhibited much
higher reactivity than that with electron-donating groups (Me,
OMe, Ph). Substituents at the otho, meta, or para positions had
no obvious effect on the reactions, although the substitution on
the otho position possessed larger steric hindrance. Disub-
stitution was also well tolerated (2aq−2as). These functional
substituent groups offered versatile handles for further
transformations. Moreover, the naphthyl substrate afforded
the desired product in 52% yield (2at). It is noteworthy that, in
all cases, only E-isomers were obtained, and no Z-isomers
could be detected by analyzing the reaction mixtures. The
structures of 2ah and 2am were confirmed by single-crystal X-
ray diffraction (see the Supporting Information).
Next, we investigated the substituents on the right aromatic
ring (Scheme 3). Delightfully, the reaction also exhibited good
compatibility of various substituent groups. Substrates bearing
Me, OMe, F, Cl, and Br all performed well, giving the desired
1,4-enediones with complete E-stereoselectivity in good to
excellent yields (61−88%, 2ba−2bl).
d
e
f
g
(57%). 30 mol % Cu(OAc)2 was used. Pd(OAc)2 (12.5 mol %).
h
Pd(OAc)2 (15 mol %).
Gratifyingly, when Cu(OAc)2 (10 mol %) as the co-catalyst
was added into the reaction system, the yield was greatly
improved to 61% (entry 2). We then carefully investigated
other Pd sources such as Pd(TFA)2, PdCl2, Pd(PPh3)4,
Pd(OH)2, and Pd2(dba)3. Pd(OAc)2 was proved to be more
effective (entries 3−7). Subsequently, various solvents were
screened, and DMSO provided a better yield (entry 9). Then
with Pd(OAc)2 as the catalyst and DMSO as the solvent, the
other co-catalysts were investigated (entries 10−14). It should
be mentioned that Cu(OAc)2·H2O, CuOAc, CuSO4, FeSO4,
and AgOAc were effective co-catalysts for the reaction, while
Cu(OAc)2 was still the best choice. Next, the amount of
Cu(OAc)2 and TFA was investigated. Cu(OAc)2 (30 mol %)
and TFA (5.0 equiv) provided the best results (entries 16−
21). The yield was improved to 82% when the loading of
Pd(OAc)2 was increased to 12.5 mol % (entry 22), while a
further increase to Pd(OAc)2 (e.g., 15 mol %) did not improve
the yield obviously (entry 23). It is worth mentioning that
replacing O2 with other hydrogen acceptors such as H2O2, 3-
chloroperbenzoic acid, or allyl acetate led to inferior yields (see
the Supporting Information). A series of control experiments
were performed. The reaction could not proceed well in the
absence of the Pd(OAc)2, Cu(OAc)2, O2, or TFA (see the
Then, we turned our attention to another kind of ketones, 5-
arylpentan-2-ones (Scheme 4). As expected, these ketones
were suitable substrates. These reactions were not sensitive to
the electronic property and the position of substituent groups
on aromatic rings. A broad range of functional groups such as
t
Me, Bu, OMe, F, Cl, and Br were compatible with these
reaction conditions, and all of the substrates delivered the
desired products in good to excellent yields (70−93%, 4a−4k).
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a,
b
a,b
Scheme 3. Substituents on the Right Aromatic Ring
Scheme 5. Scope of Other Ketones
a
Reaction conditions: 5 (0.5 mmol), Pd(OAc)2 (12.5 mol %),
Cu(OAc)2 (30 mol %), and TFA (1.25 equiv) in DMSO (2 mL) at
b
80 °C for 72 h. Isolated yields.
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (12.5 mol %),
Cu(OAc)2 (30 mol %), and TFA (5.0 equiv) in DMSO (2 mL) at 80
b
°C for 48 h. Isolated yields.
a,b
Scheme 4. Scope of Ketones with a Monoaromatic Ring
To further demonstrate the synthetic utilities of this
protocol, the direct dehydrogenation products were further
transformed into 2,5-diphenylfuran and 2,5-diphenylpyrrole
(eqs 2 and 3).2b,c The (E)-1,4-enediones were also trans-
formed into the corresponding Z-isomers by irradiation with
white light (eqs 4 and 5).4e
a
Reaction conditions: 3 (0.5 mmol), Pd(OAc)2 (12.5 mol %),
Cu(OAc)2 (30 mol %), and TFA (5.0 equiv) in DMSO (2 mL) at 80
b
°C for 48 h. Isolated yields.
To gain insight into the reaction mechanism, we carried out
a series of deuterium-labeling experiments. We conducted the
experiment with DMSO-d6 under the standard reaction
conditions, delivering the deuterium-labeling product in 3%
yield with 19% H incorporation at the α position. In addition,
the recovered [D1]-1aa was found to contain 26% H at the α
position (eq 6). The occurrence of H/D exchange in [D1]-1aa
indicated that the ketone underwent the enolization. Addi-
tionally, kinetic isotope effect (KIE) experiments were carried
out. The KIE values of two parallel reactions of the α and γ
positions were found to be 2.65 and 2.42, respectively (eqs 7
and 9). The intramolecular KIE value for the reaction of the β
position was 1.04 (eq 8). These results indicated that the
cleavage of the α-C−H and γ-C−H bond should be involved in
the rate-determining step, while the elimination of β-C−H
bond was not rate limiting. In the reaction system of
compound 1, we successively detected α,β-unsaturated ketone
(7), vinyl ketone (8), and diketone (9) (Scheme 6). Then we
Note that active cyclopropane ring was intact in the reaction,
demonstrating the reaction conditions were mild (4q). Again,
complete E-stereoselectivity for the CC double bond was
exhibited.
Finally, more challenging substrates, 1-arylpentan-1-ones,
were investigated. Pleasingly, these substrates afforded the
corresponding 1,4-enediones in 34−56% yields (Scheme 5).13
A heterocyclic substrate, such as 1-(thiophene-2-yl)pentan-1-
one (5c), was also suitable for the transformation. It was
interesting that vinyl ketone, 1-phenylhept-1-en-3-one (5d),
reacted well to give the desired product 6d in 56% yield.
However, under the current reaction conditions, 2-hexanone,
2-octanone, and cyclohexanone gave messy reactions.
To test the practicality of this method, a gram-scale reaction
was carried out. On a 4 mmol scale, the desired product 2ah
was obtained in 74% yield for 48 h. With a longer reaction
time, the yield could reach 83% (eq 1).
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Scheme 7. Proposed Mechanism
Scheme 6. Syntheses of 1,4-Enediones from Other Ketones
oxidant and represents an atom- and step-economic process.
The reaction is completely E-stereoselective and possesses
broad substrate scope and good tolerance of functional groups.
In addition, the products can be readily transformed into 2,5-
diarylfuran, 2,5-diarylpyrrole, and the corresponding Z-
isomers. Further studies to expand the reaction and their
applications as well as investigations of the detailed mechanism
are now in progress.
prepared compounds 9, 10, and 11, respectively. Under the
standard reaction conditions, α,β-unsaturated ketone (10) and
vinyl ketone (11) could tautomerize and both could generate
1,4-enedione (2ab) in 83% and 74% yields, respectively.
Diketone (9) also underwent the dehydrogenation into 1,4-
enedione (2aa) in 92% yield under the standard reaction
conditions.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04174.
■
sı
Experimental details, characterization data, copies of 1H,
13C NMR spectra, and the original HRMS analysis
reports (PDF)
On the basis of these results and the related litera-
ture,12,14−18 a tentative mechanism for the Pd-catalyzed
dehydrogenation of ketones to produce 1,4-enediones was
proposed, as shown in Scheme 7. The active Pd(O2CCF3)+ is
generated in situ by the treatment of Pd(OAc)2 with TFA.14
Simultaneously, the ketone undergoes enolization, formation
of palladium enolate, and β-hydride elimination to afford the
α,β-unsaturated ketone D and PdII-hydride intermediate that
eliminates a TFA and then is reoxidized to Pd(O2CCF3)+ by
O2 in the presence of TFA.12g−i,15 CuII can facilitate the
catalytic cycle of Pd0 to PdII.16 Then α,β-unsaturated ketone D
isomerizes into diene E. The right CC double bond of diene
E undergoes similar Wacker oxidation17,18 and thereby
generates 1,4-diketone F which then proceeds the same
palladium enolate and β-hydride elimination to produce 1,4-
enedione. The great E-stereoselectivity of the CC double
bond was ascribed to syn β-hydride elimination of palladium
enolate.12n PdII hydride intermediate proceeds by the same
process to regenerate Pd(O2CCF3)+ and complete the catalytic
cycle.
Accession Codes
CCDC 2017898 and 2038537 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Yong-Qiang Wang − Key Laboratory of Synthetic and
Natural Functional Molecule Chemistry of Ministry of
Education, Department of Chemistry & Materials Science,
Northwest University, Xi’an 710069, P.R. China;
orcid.org/0000-0002-2774-3248; Email: wangyq@
nwu.edu.cn
Authors
In conclusion, we have developed an unprecedented and
concise protocol for the synthesis of 1,4-enediones via
palladium-catalyzed oxidative dehydrogenation of saturated
ketones. The protocol employs molecular oxygen as the sole
Bao-Yin Zhao − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P.R. China
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Chem. 2008, 73, 3377. (f) Rajeshkumar, V.; Neelamegam, C.; John,
L.; Anandan, S. Metal- and solvent-free phosphine mediated synthesis
of multisubstituted furans via intramolecular annulation of 1,4-
enediones. ChemistrySelect 2018, 3, 11606.
Xing-Long Zhang − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P.R. China
(3) (a) Kaupp, G.; Schmeyers, J.; Kuse, A.; Atfeh, A. A. Cascade
reactions in quantitative solid-state syntheses. Angew. Chem., Int. Ed.
1999, 38, 2896. (b) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman,
B. M.; Deng, L. Asymmetric Diels-Alder reactions of 2-pyrones with a
bifunctional organic catalyst. J. Am. Chem. Soc. 2007, 129, 6364.
(c) Shu, W.-M.; Yang, Y.; Zhang, D.-X.; Wu, L.-M.; Zhu, Y.-P.; Yin,
G.-D.; Wu, A.-X. Highly efficient synthesis of 3a,6a-dihydrofuro[2,3-
b]furans via a novel bicyclization. Org. Lett. 2013, 15, 456. (d) Zhou,
W.; Su, X.; Tao, M.; Zhu, C.; Zhao, Q.; Zhang, J. Chiral sulfinamide
bisphosphine catalysts: design, synthesis, and application in highly
enantioselective intermolecular cross-Rauhut−Currier reactions.
Angew. Chem., Int. Ed. 2015, 54, 14853. (e) Dou, X.; Lu, Y.;
Hayashi, T. Base-free conditions for rhodium-catalyzed asymmetric
arylation to produce stereochemically labile α-aryl ketones. Angew.
Chem., Int. Ed. 2016, 55, 6739. (f) Qin, C.; Liu, Y.; Yu, Y.; Fu, Y.; Li,
H.; Wang, W. α-Functionalization of 2-vinylpyridines via a chiral
phosphine catalyzed enantioselective cross Rauhut−Currier reaction.
Org. Lett. 2018, 20, 1304.
Rui-Li Guo − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P.R. China
Meng-Yue Wang − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P.R. China
Ya-Ru Gao − Key Laboratory of Synthetic and Natural
Functional Molecule Chemistry of Ministry of Education,
Department of Chemistry & Materials Science, Northwest
University, Xi’an 710069, P.R. China; orcid.org/0000-
0002-6057-1652
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04174
(4) (a) Yin, G.; Zhou, B.; Meng, X.; Wu, A.; Pan, Y. Efficient C−C
double-bond formation reaction via a new synthetic strategy: a self-
sorting tandem reaction. Org. Lett. 2006, 8, 2245. (b) Gao, M.; Yang,
Y.; Wu, Y.-D.; Deng, C.; Shu, W.-M.; Zhang, D.-X.; Cao, L.-P.; She,
N.-F.; Wu, A.-X. An efficient synthesis of hydantoins via sustainable
integration of coupled domino processes. Org. Lett. 2010, 12, 4026.
(c) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Cao, L.-P.; Meng, X.-G.;
Wu, A.-X. Formation of unsymmetrical 1,4-enediones via a focusing
domino strategy: cross-coupling of 1,3-dicarbonyl compounds and
methyl ketones or terminal aryl alkenes. Org. Lett. 2010, 12, 1856.
(d) Zhu, Y.-P.; Cai, Q.; Gao, Q.-H.; Jia, F.-C.; Liu, M.-C.; Gao, M.;
Wu, A.-X. Target-oriented synthesis: miscellaneous synthetic routes to
access 1,4-enediones through the coupling of 1,3-dicarbonyl
compounds with multiform substrates. Tetrahedron 2013, 69, 6392.
(e) Xu, K.; Fang, Y.; Yan, Z.; Zha, Z.; Wang, Z. A highly tunable
stereoselective dimerization of methyl ketone: efficient synthesis of E-
and Z-1,4-enediones. Org. Lett. 2013, 15, 2148. (f) Meng, X.; Zhang,
J.; Chen, G.; Chen, B.; Zhao, P. Heterogeneous synthesis of 1,4-
enediones and 1,4-diketones with manganese oxide molecular sieves
OMS-2 as a recyclable catalyst. Catal. Commun. 2015, 69, 239.
(g) Satish, G.; Ilangovan, A. I2/Cu-mediated self-sorting domino
reaction of aryl β-ketoesters into symmetrical 2-carboalkoxy-1,4-
enediones: application to synthesis of pyrazine, β-carboline and
quinoxalines. RSC Adv. 2015, 5, 46163. (h) Devari, S.; Kumar, A.;
Deshidi, R.; Shah, B. A. C−H functionalization of terminal alkynes
towards stereospecific synthesis of (E) or (Z.) 2-methylthio-1,4-ene-
diones. Chem. Commun. 2015, 51, 5013. (i) Wei, D.; Liang, F. Visible-
light-mediated oxidative dimerization of arylalkynes in the open air:
stereoselective synthesis of (Z)-1,4-enediones. Org. Lett. 2016, 18,
5860. (j) Rastogi, G. K.; Deka, B.; Deb, M. L.; Baruah, P. K.
Diastereoselective sp3-C−H functionalization of arylmethyl ketones
and transformation of E- to Z-products through photocatalysis. Eur. J.
Org. Chem. 2020, 2020, 424.
(5) (a) Williams, P. D.; LeGoff, E. Enedione-functionalized
macrocycles via oxidative ring opening of furans. J. Org. Chem.
1981, 46, 4143. (b) Bailey, P. S.; Hwang, H. H. Ozonation of phenyl-
substituted thiophenes. J. Org. Chem. 1985, 50, 1778. (c) Massa, A.;
Acocella, M. R.; Rosa, M. D.; Soriente, A.; Villano, R.; Scettri, A.
Mo(CO)6-catalyzed oxidation of furan derivatives to E- and Z-
enediones by cumyl hydroperoxide. Tetrahedron Lett. 2003, 44, 835.
(d) Blank, S. J.; Stephens, C. E. Oxidative ring opening of 2,5-
diarylfurans by selectfluor. Tetrahedron Lett. 2006, 47, 6849.
(e) Nandakumar, M.; Sivasakthikumaran, R.; Mohanakrishnan, A.
K. Oxidative ring opening of 1,3-diarylbenzo[c]heterocycles using m-
CPBA: preparation of 1,2-diaroylbenzenes. Eur. J. Org. Chem. 2012,
2012, 3647. (f) Asta, C.; Conrad, J.; Mika, S.; Beifuss, U. Laccase-
catalyzed stereoselective oxidative ring opening of 2,5-dialkylfurans
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from National Natural
Science Foundation of China (Nos. NSFC-21572178, NSFC-
21702162, and NSFC-21971206).
REFERENCES
■
(1) (a) Aiello, A.; Fattorusso, E.; Magno, S.; Menna, M.; Pansini, M.
Steroids of the marine sponge cinachyra tarentina: isolation of
cholest-4-ene-3,6-dione and (24R)-24-ethylcholest-4-ene-3,6-dione. J.
Nat. Prod. 1991, 54, 281. (b) Zhang, W.-H.; Che, C.-T.
Isomalabaricane-type nortriterpenoids and other constituents of the
marine sponge geodia japonica. J. Nat. Prod. 2001, 64, 1489. (c) Lv, F.;
Deng, Z.; Li, J.; Fu, H.; van Soest, R. W. M.; Proksch, P.; Lin, W.
Isomalabaricane-type compounds from the marine sponge rhabdas-
trella aff. distincta. J. Nat. Prod. 2004, 67, 2033. (d) Cai, P.; Kong, F.;
Ruppen, M. E.; Glasier, G.; Carter, G. T. Hygrocins A and B,
naphthoquinone macrolides from Streptomyces hygroscopicus. J. Nat.
Prod. 2005, 68, 1736. (e) Fouad, M.; Edrada, R. A.; Ebel, R.; Wray,
V.; Muller, W. E. G.; Lin, W. H.; Proksch, P. Cytotoxic
̈
isomalabaricane triterpenes from the marine sponge Rhabdastrella
globostellata. J. Nat. Prod. 2006, 69, 211. (f) Lv, F.; Xu, M.; Deng, Z.;
de Voogd, N. J.; van Soest, R. W. M.; Proksch, P.; Lin, W.;
Rhabdastrellins, A.-F. isomalabaricane triterpenes from the marine
sponge Rhabdastrella aff.distincta. J. Nat. Prod. 2008, 71, 1738.
(g) Pouwer, R. H.; Deydier, S. M.; Le, P. V.; Schwartz, B. D.; Franken,
N. C.; Davis, R. A.; Coster, M. J.; Charman, S. A.; Edstein, M. D.;
Skinner-Adams, T. S.; Andrews, K. T.; Jenkins, I. D.; Quinn, R. Total
synthesis of thiaplakortone A: derivatives as metabolically stable leads
for the treatment of malaria. J. ACS Med. Chem. Lett. 2014, 5, 178.
(2) (a) Bauer, C. R.; Lutz, R. E. The conformations of the cis and
trans-dibenzoylstyrenes. J. Am. Chem. Soc. 1953, 75, 5997. (b) Surya
Prakash Rao, H.; Jothilingam, S. One-pot synthesis of pyrrole
derivatives from (E)-1,4-diaryl-2-butene-1,4-diones. Tetrahedron Lett.
2001, 42, 6595. (c) Surya Prakash Rao, H.; Jothilingam, S. Facile
microwave-mediated transformations of 2-butene-1,4-diones and 2-
butyne-1,4-diones to furan derivatives. J. Org. Chem. 2003, 68, 5392.
(d) Lu, J.; Ho, D. M.; Vogelaar, N. J.; Kraml, C. M.; Bernhard, S.;
Byrne, N.; Kim, L. R.; Pascal, R. A., Jr. Synthesis, structure, and
resolution of exceptionally twisted pentacenes. J. Am. Chem. Soc.
2006, 128, 17043. (e) Yin, G.; Wang, Z.; Chen, A.; Gao, M.; Wu, A.;
Pan, Y. A new facile approach to the synthesis of 3-methylthio-
substituted furans, pyrroles, thiophenes, and related derivatives. J. Org.
1220
https://dx.doi.org/10.1021/acs.orglett.0c04174
Org. Lett. 2021, 23, 1216−1221

Organic Letters
pubs.acs.org/OrgLett
Letter
into 2-ene-1,4-diones using air as an oxidant. Green Chem. 2011, 13,
3066.
Synthetic strategy: palladium-catalyzed dehydrogenation of carbonyl
compounds. J. Org. Chem. 2019, 84, 1687.
(13) Chen, M.; Dong, G. Copper-catalyzed desaturation of lactones,
lactams, and ketones under pH-neutral conditions. J. Am. Chem. Soc.
2019, 141, 14889.
(6) (a) Baratta, W.; Del Zotto, A.; Rigo, P. Highly stereoselective
formation of cis-enediones from α-diazo carbonyl compounds
catalysed by [RuCl(η5-C5H5)(PPh3)2]. Chem. Commun. 1997, 2163.
(b) Del Zotto, A.; Baratta, W.; Verardo, G.; Rigo, P. Functionalised
cis-alkenes from the stereoselective decomposition of diazo com-
pounds, catalysed by [RuCl(η5-C5H5)(PPh3)2]. Eur. J. Org. Chem.
2000, 2000, 2795. (c) Neuhaus, J. D.; Bauer, A.; Pinto, A.; Maulide,
N. A catalytic cross-olefination of diazo compounds with sulfoxonium
ylides. Angew. Chem., Int. Ed. 2018, 57, 16215.
(7) (a) Runcie, K. A.; Taylor, R. J. K. The in situ oxidation−Wittig
reaction of α-hydroxyketones. Chem. Commun. 2002, 974. (b) Duy
Vu, M.; Leng, W.-L.; Hsu, H.-C.; Liu, X.-W. Alkene synthesis using
phosphonium ylides as umpolung reagents. Asian J. Org. Chem. 2019,
8, 93.
(8) Crone, B.; Kirsch, S. F. A new method for the synthesis of Z-
enediones via IBX-mediated oxidative rearrangement of 2-alkynyl
alcohol systems. Chem. Commun. 2006, 764.
(9) Jadhav, A. M.; Gawade, S. A.; Vasu, D.; Dateer, R. B.; Liu, R.-S.
ZnII- and AuI-catalyzed regioselective hydrative oxidations of 3-en-1-
ynes with selectfluor: realization of 1,4-dioxo and 1,4-oxohydroxy
functionalizations. Chem. - Eur. J. 2014, 20, 1813.
(10) Yu, J.-Q.; Corey, E. J. A mild, catalytic, and highly selective
method for the oxidation of α,β-enones to 1,4-enediones. J. Am. Chem.
Soc. 2003, 125, 3232.
(11) (a) Catino, A. J.; Forslund, R. E.; Doyle, M. P. Dirhodium(II)
caprolactamate: an exceptional catalyst for allylic oxidation. J. Am.
Chem. Soc. 2004, 126, 13622. (b) McLaughlin, E. C.; Choi, H.; Wang,
K.; Chiou, G.; Doyle, M. P. Allylic oxidations catalyzed by dirhodium
caprolactamate via aqueous tert-butyl hydroperoxide: the role of the
tert-butylperoxy radical. J. Org. Chem. 2009, 74, 730.
(12) For Pd-catalyzed aerobic oxidation reactions, see: (a) Stahl, S.
S. Palladium oxidase catalysis: selective oxidation of organic chemicals
by direct dioxygen-coupled turnover. Angew. Chem., Int. Ed. 2004, 43,
3400. (b) Steinhoff, B. A.; Stahl, S. S. Mechanism of Pd(OAc)2/
DMSO-catalyzed aerobic alcohol oxidation: mass-transfer-limitation
effects and catalyst decomposition pathways. J. Am. Chem. Soc. 2006,
128, 4348. (c) Gligorich, K. M.; Sigman, M. S. Recent advancements
and challenges of palladiumII-catalyzed oxidation reactions with
molecular oxygen as the sole oxidant. Chem. Commun. 2009, 3854.
(d) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Recent advances in
transition-metal catalyzed reactions using molecular oxygen as the
oxidant. Chem. Soc. Rev. 2012, 41, 3381. (e) Ye, X.; Johnson, M. D.;
Diao, T.; Yates, M. H.; Stahl, S. S. Development of safe and scalable
continuous-flow methods for palladium-catalyzed aerobic oxidation
reactions. Green Chem. 2010, 12, 1180. (f) Izawa, Y.; Pun, D.; Stahl, S.
S. Palladium-catalyzed aerobic dehydrogenation of substituted
cyclohexanones to phenols. Science 2011, 333, 209. (g) Diao, T.;
Stahl, S. S. Synthesis of cyclic enones via direct palladium-catalyzed
aerobic dehydrogenation of ketones. J. Am. Chem. Soc. 2011, 133,
14566. (h) Diao, T.; Wadzinski, T. J.; Stahl, S. S. Direct aerobic α,β-
dehydrogenation of aldehydes and ketones with a Pd(TFA)2/4,5-
diazafluorenone catalyst. Chem. Sci. 2012, 3, 887. (i) Diao, T.; Pun,
D.; Stahl, S. S. Aerobic dehydrogenation of cyclohexanone to
cyclohexenone catalyzed by Pd(DMSO)2(TFA)2: evidence for
ligand-controlled chemoselectivity. J. Am. Chem. Soc. 2013, 135,
8205. (j) Pun, D.; Diao, T.; Stahl, S. S. Aerobic dehydrogenation of
cyclohexanone to phenol catalyzed by Pd(TFA)2/2-dimethylamino-
pyridine: evidence for the role of Pd nanoparticles. J. Am. Chem. Soc.
2013, 135, 8213. (k) Izawa, Y.; Zheng, C.; Stahl, S. S. Aerobic
oxidative Heck/dehydrogenation reactions of cyclohexenones:
efficient access to meta-substituted phenols. Angew. Chem., Int. Ed.
2013, 52, 3672. (l) Iosub, A. V.; Stahl, S. S. Palladium-catalyzed
aerobic oxidative dehydrogenation of cyclohexenes to substituted
arene derivatives. J. Am. Chem. Soc. 2015, 137, 3454. (m) Iosub, A. V.;
Stahl, S. S. Palladium-catalyzed aerobic dehydrogenation of cyclic
hydrocarbons for the synthesis of substituted aromatics and other
unsaturated products. ACS Catal. 2016, 6, 8201. (n) Hirao, T.
(14) (a) Lu, W.; Yamaoka, Y.; Taniguchi, Y.; Kitamura, T.; Takaki,
K.; Fujiwara, Y. Palladium(II)-catalyzed carboxylation of benzene and
other aromatic compounds with carbon monoxide under very mild
conditions. J. Organomet. Chem. 1999, 580, 290. (b) Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Efficient activation of
aromatic C−H bonds for addition to C−C multiple bonds. Science
2000, 287, 1992. (c) Chen, W.-L.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.;
Wang, Y.-F.; Wang, Y.-Q. Palladium-catalyzed intermolecular C3
alkenylation of indoles using oxygen as the oxidant. Org. Lett. 2012,
14, 5920.
(15) (a) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M.
J. Palladium-catalyzed intermolecular alkenylation of indoles by
solvent-controlled regioselective C−H functionalization. Angew.
Chem., Int. Ed. 2005, 44, 3125. (b) Djakovitch, L.; Rouge, P. New
homogeneously and heterogeneously [Pd/Cu]-catalysed C3-alkeny-
lation of free NH-indoles. J. Mol. Catal. A: Chem. 2007, 273, 230.
(c) Alexanian, E. J.; Hartwig, J. F. Mechanistic study of β-hydrogen
elimination from organoplatinum(II) enolate complexes. J. Am. Chem.
Soc. 2008, 130, 15627. (d) Muzart, J. One-Pot syntheses of α,β-
unsaturated carbonyl compounds through palladium-mediated
dehydrogenation of ketones, aldehydes, esters, lactones and amides.
Eur. J. Org. Chem. 2010, 2010, 3779. (e) Yeung, C. S.; Dong, V. M.
Catalytic dehydrogenative cross-coupling: forming carbon-carbon
bonds by oxidizing two carbon-hydrogen bonds. Chem. Rev. 2011,
111, 1215. (f) Gao, W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. General
palladium-catalyzed aerobic dehydrogenation to generate double
bonds. Chem. Sci. 2012, 3, 883. (g) Campbell, A. N.; Stahl, S. S.
Overcoming the “oxidant problem”: strategies to use O2 as the
oxidant in organometallic C−H oxidation reactions catalyzed by Pd
(and Cu). Acc. Chem. Res. 2012, 45, 851.
(16) (a) Wen, J.; Tang, S.; Zhang, F.; Shi, R.; Lei, A. Palladium/
Copper co-catalyzed oxidative C−H/C−H carbonylation of diphenyl-
amines: a way to access acridones. Org. Lett. 2017, 19, 94. (b) Liu, X.;
Mao, R.; Ma, C. Crossover-annulation/oxygenation approach to
functionalized phenanthridines by palladium−copper relay catalysis.
Org. Lett. 2017, 19, 6704.
(17) (a) Zhang, Z.; Pan, C.; Wang, Z. Synthesis of chromanones: a
novel palladium-catalyzed Wacker-type oxidative cyclization involving
1,5-hydride alkyl to palladium migration. Chem. Commun. 2007, 4686.
(b) Sigman, M. S.; Werner, E. W. Imparting catalyst control upon
classical palladium-catalyzed alkenyl C−H bond functionalization
reactions. Acc. Chem. Res. 2012, 45, 874. (c) Wang, Y.-F.; Gao, Y.-R.;
Mao, S.; Zhang, Y.-L.; Guo, D.-D.; Yan, Z.-L.; Guo, S.-H.; Wang, Y.-
Q. Wacker-type oxidation and dehydrogenation of terminal olefins
using molecular oxygen as the sole oxidant without adding ligand.
Org. Lett. 2014, 16, 1610.
(18) For the Wacker oxidation mechanism, see: (a) Keith, J. A.;
Oxgaard, J.; Goddard, W. A. Inaccessibility of β-hydride elimination
from -OH functional groups in Wacker-type oxidation. J. Am. Chem.
Soc. 2006, 128, 3132. (b) Keith, J. A.; Nielsen, R. J.; Oxgaard, J.;
Goddard, W. A. Unraveling the Wacker oxidation mechanisms. J. Am.
Chem. Soc. 2007, 129, 12342. (c) Cornell, C. N.; Sigman, M. S.
Recent progress in Wacker oxidations: moving toward molecular
oxygen as the sole oxidant. Inorg. Chem. 2007, 46, 1903. (d) Keith, J.
A.; Henry, P. M. The mechanism of the Wacker reaction: a tale of two
hydroxypalladations. Angew. Chem., Int. Ed. 2009, 48, 9038.
(e) Anderson, B. J.; Keith, J. A.; Sigman, M. S. Experimental and
computational study of a direct O2-coupled Wacker oxidation: water
dependence in the absence of Cu salts. J. Am. Chem. Soc. 2010, 132,
11872.
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Org. Lett. 2021, 23, 1216−1221