Dual Role of H2O2 in Palladium-Catalyzed Dioxygenation of Terminal Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b01228

A palladium-catalyzed, environmentally friendly dioxygenation reaction of simple alkenes has been developed that enabled rapid assembly of valuable α-hydroxy ketones with high atom economy. Notably, control experiments and ¹⁸O isotope-labeling experiments established that H₂O₂ played a dominant dual role in this transformation.

Full text of DOI:10.1021/acs.orglett.7b01228

Letter
pubs.acs.org/OrgLett
Dual Role of H2O2 in Palladium-Catalyzed Dioxygenation of Terminal
Alkenes
Jiuzhong Huang, Jianxiao Li, Jia Zheng, Wanqing Wu,* Weigao Hu, Lu Ouyang, and Huanfeng Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed, environmentally friendly
dioxygenation reaction of simple alkenes has been developed
that enabled rapid assembly of valuable α-hydroxy ketones
with high atom economy. Notably, control experiments and
18O isotope-labeling experiments established that H2O2 played a dominant dual role in this transformation.
Scheme 1. Pd-Catalyzed Dioxygenation of Alkenes
he α-hydroxy ketone moieties have been recognized as
Tprivileged structural motifs with diverse biological and
medicinal applications1 and have also found broad use in
organic chemistry.2 As a consequence, many representative
methods have been developed for constructing this scaffold
from the readily available olefins. Early studies were initiated by
RuO4-catalyzed ketohydroxylation reaction of alkenes with
Oxone as oxidant.3a,b Recently, Wu’s group demonstrated
stoichiometric iodine-promoted activation and oxidation of
alkenes to synthesize α-hydroxy ketones.3c Thus, the develop-
ment of an efficient and environmentally benign process is still
highly appealing and in demand.
The dioxygenation of alkenes has emerged as one of the
most attractive and powerful strategies for efficient construction
of two C−O bonds with maximal atom and step economy in
recent years. Since Sharpless’ seminal discovery of asymmetric
dihydroxylation of alkenes via a ligand-accelerated process,
extensive efforts have been devoted to develop efficient
methods for this type of transformation.4 In this regard,
palladium-catalyzed dioxygenation of alkenes has become one
of the most attractive and fascinating areas in contemporary
organic synthesis.5 In general, the chemical conversion was
triggered by oxypalladation (Wacker-type process),6 and then
the high-valent Pd intermediates were generated under an
oxidant such as hypervalent iodine reagents,5a,b nitrite,5c,d
peroxy acid,5e and molecular oxygen,5f,h etc., which released the
products with two newly formed C(sp3)−O bonds at last
(Scheme 1).7 Most notably, applying the environmentally
benign oxidants is the persistent goal for synthetic chemists.8,9
Representatively, our group successfully developed the first
example of Pd-catalyzed diacetoxylation of alkenes using
molecular oxygen as the sole oxidant, which opens up a new
sight for the green synthesis.5f On the other hand, the Liu
group has comprehensively reported Pd-catalyzed chloroami-
nation and oxyamination of alkenes by “green” H2O2 as the
oxidant.10 Inspired by the aforementioned background and our
longstanding interest in Pd-catalyzed difunctionization of
olefins,11 we disclose herein a Pd-catalyzed dioxygenation of
alkenes to construct α-hydroxy ketones with H2O2 as oxidant
and oxygen source. Remarkably, the H2O2 played two
distinguished roles to afford C(sp2)−O and C(sp3)−O bond
formations across the reaction.
We initiated the investigation using 4-tert-butylstyrene as
substrate in the presence of 7.5 mol % of Pd(OAc)2 and 3.0
equiv of H2O2 in AcOH at room temperature, which afforded
α-hydroxy ketone 2c in 5% yield (Table 1, entry 1). However,
α-acetate ketone 3c was the major product. Next, the use of
cosolvents showed little improvement in the efficiency, and
AcOH was unnecessary for the formation of 2c (Table 1,
entries 2−4, 8). In regard to acidic additives, compared with 10-
camphorsulfonic acid (10-CSA) and trifluoromethanesulfonic
acid (TfOH), the addition of trifluoroacetic acid (TFA)
obviously increased the selectivity and yield (Table 1, entries
5−7). To suppress the mono-oxidative side reaction (Wacker
product), a series of bidentate N-containing ligands were
screened. The reaction was almost completely inhibited at
room temperature when L1 (bpy) was added, which only gave
the desired product in 9% yield, and 90% of the starting
material 1c was recovered simultaneously (Table 1, entry 9).
Elevating the reaction temperature exhibited exciting results,
which afforded the desired product 2c in 65% yield at 75 °C
(Table 1, entries 10 and 11). Further examination of other
ligands such as 1,10-phenanthroline (phen, L2), diazafluor-
enone (DAF, L3), and dipyridinyl ketone (dpk, L4) proved
Received: April 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01228
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Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Pd-Catalyzed Dioxygenation of Alkenes
b
yield (%)
temp
entry additive
L
solvent (v/v)
AcOH
(°C)
2c
3c
15
1
2
rt
rt
5
AcOH/CH3CN
(1/1)
ND
16
3
4
AcOH/CH3NO2
(1/1)
rt
trace
15
AcOH/THF (1/1)
AcOH/THF (1/1)
AcOH/THF (1/1)
AcOH/THF (1/1)
THF
rt
rt
15
34
13
5
5
TFA
6
10-CSA
TfOH
TFA
rt
ND
ND
43
8
ND
ND
ND
ND
ND
ND
ND
ND
ND
7
rt
8
rt
9
TFA
L1 THF
L1 THF
L1 THF
L2 THF
L3 THF
L4 THF
rt
10
11
12
13
14
TFA
50
75
75
75
75
50
65
60
TFA
TFA
c
TFA
80 (76)
74 (73)
TFA
a
Reaction conditions: olefins 1 (0.30 mmol), Pd(OAc)2 (7.5 mol %),
a
Reaction conditions: 1c (0.3 mmol), Pd(OAc)2 (7.5 mol %), H2O2
DAF (10 mol %), TFA (2.0 equiv), H2O2 (3.0 equiv) in THF (0.15
M) with sealed tube at 75 °C for 6 h, isolated yield. On 0.10 mmol
scale. On 0.20 mmol scale.
(3.0 equiv), solvent (1.0 mL) with sealed tube for 6 h; additives (2.0
b
equiv) were added; L (10 mol %) was added; ND = not detected.
c
b
Yields determined by GC with n-dodecane as internal standard.
c
Isolated yield is in the parentheses.
Subsequently, in view of the importance of α-hydroxy ketone
in organic synthesis, a series of further transformations of
product 2a were carried out as shown in Scheme 3. For
that L3 was most suitable for the transformation (Table 1,
entries 12−14). On the basis of the above results, the optimal
reaction conditions for this dioxygenation process are Pd-
(OAc)2 (7.5 mol %), DAF (10 mol %), H2O2 (3.0 equiv) in
THF at 75 °C for 6 h (see the Supporting Information (SI) for
details).
a
Scheme 3. Selected Transformations of 2a
With satisfactory conditions in hand, we examined the scope
of the dioxygenation reaction by testing a series of terminal
alkene substrates containing various substitution patterns and
diverse functional groups. Moderate to good yields were
obtained when a broad range of electron-rich styrenes were
employed (2b−e,j,l,n) (Scheme 2). Electron-poor styrenes
were also successfully converted to the desired products with
acceptable isolated yields (2f−i) (Scheme 2). Ortho-substituted
styrenes were transferred to the target products with obviously
lower yields than those of the para- and meta-substituted
styrenes (2u−w) (Scheme 2), which might be due to the steric
hindrance. In addition, more complex substrate 1y was
compatible under the standard conditions and provided the
desired product 2y in 85% yield. Notably, the heteroaromatic
substrates successfully converted into the corresponding α-
hydroxy ketones (2z−ac) (Scheme 2). Gratifyingly, non-
activated olefins were also able to afford the products in
moderate yields (2ad−ak) (Scheme 2). Moreover, tert-hydroxy
could be observed under the acidic conditions (Scheme 2, 2ag).
Specifically, 2c and 2l could be obtained in 65% and 66% yields
in a gram-scale experiment. The products 2af and 2ag emitted
the smell of cumin, which may have a latent application value
for spices.12
a
Reaction conditions: see the SI for details.
example, the Cu-catalyzed one-pot approach toward ynedione
4, which is a powerful synthetic building block for specific
heterocycles, has been achieved with good yield (Scheme 3, eq
1). The C3-dicarbonylation of indoles was also realized under
the treatment of CuTC (Scheme 3, eq 2). Moreover, a
potentially bioactive 2-phenylquinoxaline skeleton 6 could be
prepared from 2a via a metal-free catalysis method in 92% yield
(Scheme 3, eq 3).
To gain a better understanding of this transformation, some
control experiments were conducted. Under the standard
conditions, no desired product was detected in the oxidation of
possible reaction intermediates such as 1-phenylethane-1,2-diol
7 and acetophenone 8 (Scheme 4).13 Thus, we postulated that
the plausible pathway involved the formation of peroxide,
which went through nucleophilic attack by hydrogen peroxide
B
DOI: 10.1021/acs.orglett.7b01228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of above results and literature precedents, we
postulate a tentative mechanism for the dioxygenation of
alkenes in Scheme 7. Initially, Pd(OAc)2 coordinates with
Scheme 4. Control Experiments
Scheme 7. Tentative Mechanism
on the carbon of epoxide or CC bond. We found that the
epoxide 9 and hydroxyperoxy alcohol 1014 converted into the
product 2a under the standard reaction conditions, with 34%
and 76% yields, respectively. Furthermore, compound 10 could
transfer to 2a in the absence of H2O2. Therefore, neither
compounds 7 and 8 nor the epoxide 9 were possible
intermediates, as 9 exhibited lower yield and a more complex
system than that of styrene.
In order to further verify our hypothesis, we treated the
disubstituted terminal olefins with standard conditions. The
reactions of α-methylstyrenes (11a, 11b) (Scheme 5) could
ligand DAF. The Pd(II)/DAF complex was then oxidized by
H2O2 to generate the key peroxy Pd complex Int-A,15 in which
acid would promote the dissociation of OAc− from the
palladium center. Next, cis-oxypalladation of alkene produced
the alkylpalladium species Int-B, which is consistent with the
effect of steric hindrance.16 The transient 5-membered Pd(II)
Int-B could be oxidized to the corresponding Pd(IV) Int-C by
a second molecular of H2O2, followed by reductive elimination
to release hydroxyperoxide Int-E.17 Dehydration of Int-E
occurs to give the α-hydroxy ketone product. In the other
scenario, Int-B converts into α-ketone alkyl-Pd(IV) Int-D by
the oxidation of the intramolecular peroxy bond, which
transfers directly to α-hydroxy ketone by natural reductive
elimination. Additionally, we detected Pd(DAF) (OAc)OH by
HRMS-ESI, which should be decomposed from Int-A (see the
SI for details).
In summary, a novel and practical Pd-catalyzed dioxygena-
tion of alkenes has been developed. In addition, the
dioxygenation reaction presents a method of utilizing H2O2
as the oxidant and the oxygen source. As a result, the α-hydroxy
ketones could be prepared from readily available raw materials,
which will inspire new designs of the difunctionalization of
alkenes. Further mechanistic studies, the scope of the reaction,
and the further difunctionalization reaction of alkenes using
green oxidants are in process in our laboratory.
Scheme 5. Disubstituted Terminal Olefins under Standard
Conditions
also proceed smoothly to provide the corresponding α-hydroxy
ketones. Meanwhile, 1,1-diphenylethene 12 could be converted
to benzophenone 13 under the optimized conditions, albeit
with somewhat reduced yield. All of these results suggested that
hydroxyperoxide intermediates might be possible intermediates
in this chemical process.
Next, the isotope-labeling experiments were performed.
When urea/H2O2 and H218O were used instead of H2O2 aq
under the standard conditions, product 2a with 26% mono-18O
label was detected by HRMS-ESI (Scheme 6) (see the SI for
Scheme 6. 18O-Labeling Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01228.
Experimental procedures, condition screening table,
characterization data, and NMR spectra for all products
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
details). Interestingly, 2a was transferred to α-bromo ketone 14
without 18O incorporation. Hence, it is supposed that the
oxygen atoms of carbonyl and hydroxyl were derived from
H2O2. Notably, the palladium(IV) complex might be involved
in the formation of C−OH bond via the direct reductive
elimination (SN1 type nucleophilic attack) as a major pathway.
*E-mail: jianghf@scut.edu.cn.
*E-mail: cewuwq@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
C
DOI: 10.1021/acs.orglett.7b01228
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Program on Key Research Project
(2016YFA0602900), the National Natural Science Foundation
of China (21420102003 and 21672072), and the Fundamental
Research Funds for the Central Universities (2015ZY001 and
2017ZD062) for financial support.
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DOI: 10.1021/acs.orglett.7b01228
Org. Lett. XXXX, XXX, XXX−XXX