B2pin2-Mediated Palladium-Catalyzed Diacetoxylation of Aryl Alkenes with O2 as Oxygen Source and Sole Oxidant

Article abstract of DOI:10.1021/acs.orglett.8b01806

A novel palladium-catalyzed alkene diacetoxylation with dioxygen (O₂) as both the sole oxidant and oxygen source is developed, which was identified by ¹⁸O-isotope labeling studies. Control experiments suggested that bis(pinacolato)diboron (B₂pin₂) played a dominant intermediary role in the formation of a C-O bond. This method performed good functional group tolerance with moderate to excellent yields, which could be successfully applied to the late-stage modification of natural products. Furthermore, an atmospheric pressure of dioxygen enhances the practicability of the protocol.

Full text of DOI:10.1021/acs.orglett.8b01806

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
B2pin2‑Mediated Palladium-Catalyzed Diacetoxylation of Aryl
Alkenes with O2 as Oxygen Source and Sole Oxidant
Jiuzhong Huang, Lu Ouyang, Jianxiao Li, Jia Zheng, Wuxin Yan, Wanqing Wu, 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 novel palladium-catalyzed alkene diacetoxylation
with dioxygen (O2) as both the sole oxidant and oxygen source is
developed, which was identified by 18O-isotope labeling studies.
Control experiments suggested that bis(pinacolato)diboron (B2pin2)
played a dominant intermediary role in the formation of a C−O
bond. This method performed good functional group tolerance with moderate to excellent yields, which could be successfully
applied to the late-stage modification of natural products. Furthermore, an atmospheric pressure of dioxygen enhances the
practicability of the protocol.
xidative transformation is challenging due to its poor
selectivity and produces significant quantities of
Scheme 1. Pd-Catalyzed Aerobic Oxidation of Olefins
O
unwanted byproducts derived from the stoichiometric strong
oxidants.1 As a gentle oxidant, molecular oxygen exhibits
enormous appeal due to its nature, low cost, and sustainability
in transition-metal-catalyzed oxidation reactions, especially in
palladium catalysis.2 Although there are various examples that
the metal catalysts could be directly reoxidized by oxygen, the
metal-catalyzed aerobic oxidation fails at times because of the
low solubility of oxygen in organic solvent and the slow
electron transfer between metal to O2 in comparison with the
decomposition of the low valent metal catalyst.3
Palladium-catalyzed selective aerobic oxidation of olefins
into value-added products is one of the most important
transformations in modern organic synthesis. One of the major
challenges that remains in the selective aerobic oxidation of
olefin is to accelerate the regeneration of the PdII catalyst and
suppress the precipitation of palladium black. Since the seminal
discovery of palladium/copper-catalyzed aerobic oxidation of
olefins (Wacker oxidation),4 in which copper salt acts as the
electron transfer mediator (ETMs), extensive efforts have been
devoted to exploring efficient ETMs as a co-oxidant in recent
decades.5 For example, Grubbs and Kang independently
possible Pd−H species and prevents the deactivation of
catalyst (Scheme 1, eq 3).
After detailed examinations of different parameters,9,10 the
best conditions for the diacetoxylation reaction are as follows:
Pd(OAc)2 (7.5 mol %), terpy (10 mol %), B2pin2 (1.2 equiv),
and AcOH (5 equiv) in CH3CN/Ac2O (0.15 M, v/v = 1:1) at
90 °C under an O2 balloon (see the Supporting Information
for details). With the optimized reaction conditions in hand,
we sought to explore styrenes containing diverse functional
groups. As shown in Scheme 2, substitutions in the para
position with both electron-donating and -withdrawing groups
(EWGs) were tolerated, and these styrenes transferred to the
corresponding products with good to excellent yields (2a−2i).
It is noteworthy that the reaction time of substrates with
EWGs was longer than those with electron-donating groups
(EDGs) for improving the conversion rate. Furthermore, the
styrenes with benzyl chloride 2k and alkynyl moieties (2x)
t
reported AgNO2 and BuNO2 as ETMs to realize selective
aldehyde and ketone formation (Scheme 1, eq 1).6a,c This
approach has also been utilized in difunctionalization of olefins,
in which nitrite was used as ETMs.6b,d A high pressure of
oxygen is another strategy to increase the rate of reoxidation of
palladium species (Pd0 or Pd−H). Kaneda and co-workers
reported the Wacker process with the PdCl2−DMA system
under 6 atm of oxygen.7a The diacetoxylation of olefin under 8
atm of oxygen was demonstrated by our group.7b,c Herein, we
report a B2pin2-mediated palladium-catalyzed diacetoxylation
of olefin under 1 atm of oxygen, in which the C−O bond is
rapidly formed by aerobic oxidative C−B bond cleavage
instead of the disfavored palladium-mediated C−O bond
reductive elimination.8 Meanwhile, the ligand stabilizes the
Received: June 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Substrate Scope of Terminal Alkenes
Scheme 3. Substrate Scope of Internal Alkenes
a
Reaction conditions: alkenes 1 (0.3 mmol), Pd(OAc)2 (7.5 mol %),
terpy (10 mol %), B2pin2 (1.2 equiv), AcOH (5.0 equiv) in CH3CN/
Ac2O (0.15 M, v/v = 1:1) in reaction tube with O2 balloon at 90 °C.
The reaction time depended on different substrates by TLC
detection. Isolated yields are reported as a mixture of syn/anti-
products. The ratios of syn and anti products were determined by 1H
NMR or isolated yields. Unless otherwise noted, double bonds are E
b
c
configuration. Substrates is Z configuration. Substrates is E
d
configuration. Substrate 1ah is a Z/E (1:5.2) mixture.
a
Reaction conditions: alkenes 1 (0.3 mmol), Pd(OAc)2 (7.5 mol %),
terpy (10 mol %), B2pin2 (1.2 equiv), AcOH (5.0 equiv) in CH3CN/
Ac2O (0.15 M, v/v = 1/1) with O2 balloon at 90 °C. The reaction
time depended on different substrates by TLC detection. Isolated
yield.
eoselectivity was also consistent with the electric nature of
olefins (2ao−2ar).
In order to test the applicability and universality of this
protocol a complex structural system, the late-stage mod-
ification of natural product derivatives was implemented. The
styrenes derived from estrone, cholesterol, and glucose were
subjected to the optimized conditions (Scheme 4). Gratify-
ingly, the diacetoxylation reaction proceeded smoothly to
afford 2as, 2at, and 2au with 78%, 55%, and 67% yields,
respectively. Importantly, excellent diastereoselectivity was
observed in these transformations.
proceeded smoothly under the standard conditions. Addition-
ally, meta-, ortho-, and multisubstituted styrenes also exhibited
good reactivities to afford the target products 2l−2v in
moderate to good yields. When the conjugated diene substrate
2y was employed under the standard conditions, diacetox-
ylation of the terminal double bond was observed, while the
internal double bond was retained, which showed exclusive
regioselectivity.11 Notably, sulfur-, nitrogen-, and oxygen-
containing heteroaromatic ethenes could be also converted
into the desired products with satisfactory yields (2z−2ae).
Next, the scope of aromatic internal alkenes was examined.
When β-methylstyrene derivatives were employed in the
reaction, the desired products were obtained with anti-
diastereoselectivity to a certain extent, especially for the
electron-deficient double bonds (2af−2ai, Scheme 3). Besides,
the Z/E configuration of double bond has a small influence on
the diastereoselectivity of products (2af, 2aj), which indicated
that the formation of two C−O bonds was a multistep process.
The group of triflate, benzyl ether, and alkyl ester could be
tolerated under the standard conditions (2ah, 2aj, 2ak). The
transformation of (E,E)-1,4-diphenyl-1,3-butadiene gave the
desired product 2al with a single double bond reserved in 90%
total yield. Inactive double bonds were inert under the current
conditions (2am, 2an). Finally, trisubstituted and cyclic
internal alkenes showed good reactivity under the standard
conditions, despite an extended reaction time. The diaster-
a
Scheme 4. Diversification of Natural Product Derivatives
a
Reaction conditions: alkenes 1 (0.1 mmol), Pd(OAc)2 (7.5 mol %),
terpy (10 mol %), B2pin2 (1.2 equiv), AcOH (5.0 equiv) in CH3CN/
Ac2O (0.15 M, v/v = 1/1) in reaction tube with O2 balloon at 90 °C.
The reaction time depended on different substrates by TLC
1
detection. Isolated yield. The ratios of dr were determined by H
NMR analysis.
B
DOI: 10.1021/acs.orglett.8b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To gain deep sight into this transformation, some control
experiments and isotope labeling studies were conducted.
When phenethyl borate 4 was employed under the standard
conditions, the acetoxylation product 5 of the borate group
was isolated in 92% yield, which had never been reported until
now (Scheme 5, eq 4). In the crossover experiment, when
Scheme 6. Proposed Mechanism
Scheme 5. Mechanistic Investigations
D.10b,14 Next, O2 was directly inserted into the palladium-
hydride intermediate D to afford a palladium hydroperoxide
species E,3e,g which facilitated the oxidation of the C−B bond
of compound 10 similar to the process of hydroboration−
oxidation via the transient state F.15 Subsequently, the complex
F liberated the precursor 11 of the diacetoxylation product and
palladium complex G, which underwent ligand exchange with
AcO− to regenerate the palladium species A and H2O. The
hydroxyacetate 11 could be detected by HRMS-ESI in the
reaction mixture.
Next, the hydroxyacetate 11 could be quickly transformed
into the major single labeled product via direct acetylization by
Ac2O (Scheme 6II, path 1) or SN1 nucleophilic substitution
(path 2), which depended on the steric hindrance and
electronic effect from the results of substrate scope. Therefore,
the isotope unlabeled products were delivered from
nucleophilic substitution of AcO−, while the double isotope
labeled products were derived from the acetoxypalladation and
later direct acetylization (path 1) or the acetoxypalladation and
later nucleophilic substitution (path 2), with 18O-labeled
AcO−.
using the mixture of acetic anhydride and propanoic anhydride
in place of acetic anhydride, four products 7, 8a, 8b, and 9
were obtained in 25%, 24%, 13%, and 12% yields, respectively,
which suggested that two ester groups were installed through
independent steps during the reaction (Scheme 5, eq 5).
Furthermore, when meso-3ai was subjected to the standard
conditions, the diacetoxylation product 2ai was obtained with
higher yield and similar diastereoselectivity compared with that
of 1ai serving as the substrate (Scheme 5, eq 6). This result
indicated that the hydroxyl could be acetylized under the
standard conditions via the possible carbocation.
A subsequent 18O-labeling experiment gave the unlabeled
diacetoxylation product 2a (27.2%), mono 18O-labeled product
(61%), and doubly 18O-labeled product (12%), which were
determined by high resolution mass spectrometry (Table
1).12a,b After hydrolysis of the isotopic mixture 2a, the oxygen-
Table 1. 18O-Labelling Experiments
In summary, we have successfully developed a unique
palladium-catalyzed diacetoxylation process of alkenes with
atmospheric pressure dioxygen as both the oxygen source and
sole oxidant, in which B2pin2 plays an important intermediary
role in the formation of the C−O bond via the oxidative
cleavage of the C−B bond. Consequently, a diverse range of
functional groups were shown to be compatible with the
chemo- and diastereoselective process. The present method
also exhibits potential application value in the late-stage
modification of natural products. We believe that the strategy
of direct activation of dioxygen to realize a variety of
difunctionalization of alkene will be available soon.
isotopic mix
unlabeled
single 18O-labeled
doubly 18O-labeled
2a, abundance (%)
3a, abundance (%)
27.2
60.9
11.9
26.6
62.4
11.0
18 abundance was almost retained, which demonstrated that
the 18O label was incorporated into the C(sp3)−O bond and
the acyl groups were derived from anhydride. More
importantly, dioxygen as an oxygen source was involved in
the formation of the target product.
Based on the above results and the literature precedents,7b,12
a proposed mechanism is shown (Scheme 6I). The reaction
was initiated by trans-acetoxypalladation with alkene 1 to
provide organopalladium intermediate B, which was sequen-
tially transmetalated with B2pin2 to form the intermediate
C.12a,b,13 The intermediate C might promote the H atom
transfer from AcOH to palladium, forming [Pd−H] species
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.8b01806.
C
DOI: 10.1021/acs.orglett.8b01806
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, condition screening table,
Letter
(6) (a) Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2013, 52, 11257−11260. (b) Wickens, Z. K.; Guzman, P. E.;
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characterization data, and copies of NMR spectra for
all products (PDF)
AUTHOR INFORMATION
■
(7) (a) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.;
Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45,
481−485. (b) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009,
131, 3846−3847. (c) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75,
2321−2326.
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Notes
(8) (a) Huang, L.; Wang, Q.; Liu, X.; Jiang, H. Angew. Chem., Int. Ed.
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The authors declare no competing financial interest.
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12236−12239. (d) Grennberg, H.; Backvall, J. E. Chem. - Eur. J. 1998,
ACKNOWLEDGMENTS
■
4, 1083−1089.
The authors are grateful to Dr. Liangbin Huang (University of
Wisconsin−Madison) for helpful suggestions on this manu-
script and thank the National Program on Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21420102003), and the Fundamental
Research Funds for the Central Universities (2015ZY001) for
financial support.
(9) (a) Zhu, M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010,
132, 6284−6285. (b) Kou, X.; Li, Y.; Wu, L.; Zhang, X.; Yang, G.;
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DOI: 10.1021/acs.orglett.8b01806
Org. Lett. XXXX, XXX, XXX−XXX