Copper-/Cobalt-Catalyzed Highly Selective Radical Dioxygenation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.5b01223

A highly selective radical dioxygenation of alkenes using hydroxamic acid and O₂ was developed, and copper/cobalt was used as the catalyst without assistance of any additional ligands or bases. Mechanistic investigation disclosed that copper sa

Full text of DOI:10.1021/acs.orglett.5b01223

Letter
pubs.acs.org/OrgLett
Copper-/Cobalt-Catalyzed Highly Selective Radical Dioxygenation of
Alkenes
Qingquan Lu,† Zhiliang Liu,† Yi Luo,† Guanghui Zhang,† Zhiyuan Huang,† Huamin Wang,† Chao Liu,†,∥
Jeffrey T. Miller,§,∥ and Aiwen Lei*,†,‡,∥
†College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, Hubei, P. R.
China
‡National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China
§Department of Chemical Engineering, Purdue University, West Lafayette, Indiana 47907, United States
∥Chemical Sciences and Engineering Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439,
United States
S
* Supporting Information
ABSTRACT: A highly selective radical dioxygenation of
alkenes using hydroxamic acid and O2 was developed, and
copper/cobalt was used as the catalyst without assistance of
any additional ligands or bases. Mechanistic investigation
disclosed that copper salt and O2 work in concert to activate
hydroxamic acid, with Cu(I) and Cu(II) concurrently existing
in this reaction.
strated by Alexanian and co-workers,8 in which various alcohols
s a classic arsenal in synthetic chemistry, radical chemistry
Ahas experienced a renaissance with the upsurge of interest in
could be typically furnished after reductant workup. Owning to
transition-metal catalysis and photocatalysis.1 To date, one of the
our continuous interests in O2 activation and abundant metal
most important challenges for chemists in radical chemistry is to
catalysis,9 we present herein our recent progress in radical
dioxygenation of alkenes using copper or cobalt as the catalyst, in
which versatile α-oxyketones and α-oxo tertiary alcohols can be
synthesized in a single process (Scheme 1).
develop new methods to control the reaction selectivity more
effectively.2 However, high reactivity as well as the instability of
the radical intermediates makes this target especially challeng-
ing.1,2 In this regard, abundant metal catalysis employing
molecular oxygen as the terminal oxidant is particularly valuable
due to its availibility, minimal toxicity, and mild conditions.3 This
type of catalysis exhibits intriguing catalytic activities and
represents a promising way to tune selectivity in radical
chemistry.
Scheme 1. Radical Dioxygenation of Alkenes
Radical reactions of hydrocarbons, especially for the radical
“oxygenase-type” reactions, have attracted increasing attention
since prefunctionalization of the reactive site is unnecessary and
oxygen can be directly incorporated into the desired molecules.4
In just the past few years, various hydrocarbons have been
successufully utilized in cascade oxygenation of alkenes.5
However, the chemical selectivity of these transformations is
generally limited to the comparatively stable radical precursors
with assistance from numerous additives. Successful examples for
the reactions using O-nucleophiles are quite limited.6,7 For
reactive radical precursors, the final product is often difficult to
predict, and a mixture of hydroperoxides, alcohols, and ketones is
usually obtained.5 Until now, strategies aimed at controlling
cascade oxygenation of alkenes have been rudimentary. More-
over, in-depth mechanistic understanding of these processes
remains poor, limiting further design of new reactions.
Initially, we chose styrene (1a) and methyl N-hydroxy-N-
phenylcarbamate (2a) as the reactants to investigate the effect of
metal catalysts. Not surprisingly, only 7% yield of ketone (3a)
was formed, while secondary alcohol (4a) was observed as the
major product in the absence of any catalyst (Table 1, entry 1).8
Subsequently, we added copper salts as the catalyst precursor to
tune the reaction selectivity. It was found that the chemical
selectivity of this reaction was switched as expected. A 65% yield
of ketone (3a) was produced, while only a trace amount of
secondary alcohol was detected (entry 2). Further screening
showed that CuCl was the best catalyst precursor, and a similar
Recently, vicinal dioxygenation of alkenes by capitalizing on
Received: April 26, 2015
the vigorous reactivity of hydroxamic acid has been demon-
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01223
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Letter
a
Table 1. Survey of the Reaction Conditions
entry
catalyst
CuCl
temp (°C) yield of 3a (%) yield of 4a (%)
b
1
70
70
70
70
70
70
60
60
60
7
28
2
3
4
5
65
trace
23
Cu2O
34
CuCl2
53
trace
trace
trace
trace
trace
0
Cu(TFA)2
CuCl/Cu(TFA)2
CuCl
44
c
6
46
67 (65)
46
7
d
8
CuCl
e
9
CuCl
0
a
Unless otherwise specified, all reactions were carried out using 1a
(0.2 mmol), 2a (0.3 mmol), and catalyst (0.02 mmol) in DMSO (2.0
mL) for 4 h under O2 (balloon); yield was determined by HPLC;
Figure 1. EPR spectra for 2a (0.3 mmol) in DMSO (2.0 mL) at 60 °C
for 10 min under different conditions: (A) under O2; (B) CuCl2 (0.3
mmol) under N2; (C) CuCl (0.3 mmol) under N2; (D) CuCl (0.03
mmol) under O2.
b
isolated yield in parentheses. Yield was determined after workup with
c
d
e
PPh3. CuCl (5% mol) and Cu(TFA)2 (5% mol). Under air. Under
N2.
yield was obtained by performing the reaction at 60 °C without
any loss of reaction selectivity (entries 3−7). It is notable that
46% yield of 3a was obtained when the reaction was conducted
under air, while no product was formed under N2. The sharp
difference between these two reactions demonstrated the
importance of O2 in this process (entries 8 and 9). To further
probe the role of O2, the reaction between 1a and 2a under 18O2
was carried out (Scheme 2), and 18O-labeled product 3a was
isolated in 58% with 85% isotopic purity, indicating the carbonyl
oxygen atom of the ketone came from O2.
Figure 2. Kinetic profiles for the reaction of styrene 1a (0.4 mmol), 2a
(0.6 mmol), and different copper salt (0.04 mmol) in DMSO (4.0 mL)
at 60 °C for 4 h under O2 (balloon). (A) CuCl2. (B) CuCl.
Scheme 2. 18O2 Isotope Labeling Experiment
To gain insight into the reaction mechanism, electron
paramagnetic resonance (EPR) experiments were next con-
ducted. As shown in Figure 1, no obvious signal of amidoxyl
radical was observed when 2a was treated only with O2 (Figure
1A), CuCl2 (Figure 1B), or CuCl (Figure 1C), respectively. On
the contrary, the distinct EPR signal of amidoxyl radical was
detected when 2a was treated with O2 and CuCl (Figure 1D).
These results revealed that copper salt and O2 work synergisti-
cally to activate hydroxamic acid, initiating the radical cascade
reaction.
To acquire further understanding of the reaction mechanism,
we attempted to use operando IR to monitor the reaction
between 1a and 2a in the presence of CuCl2 or CuCl,
respectively. The kinetic profiles of relative absorbance
(ConcIRT) versus time for 1a are shown in Figure 2. Clearly,
an inductive period was observed when copper(I) was used as the
catalyst precursor.10
Figure 3. XANES spectra of 1a (4.0 mmol), 2a (6.0 mmol), and CuCl
(0.4 mmol) in DMF (4.0 mL) at 60 °C under air for 15 min (A) and its
first derivation (B).
the existence of Cu(II) in this transformation was also confirmed
by EPR. The classic Cu(II) signal can be obviously observed (for
details, see the Supporting Infomation). These results indicate
that Cu(I) and Cu(II) existed concurrently in this reaction.
On the basis of the aforementioned results and previous
studies,5 a plausible mechanistic pathway is proposed in Scheme
3. Initially, copper(I) can be oxidized to copper(II) by O2. Then,
copper(II)/copper(I) works in conjunction with O2 to activate
hydroxamic acid 2a, generating amidoxyl radical I. Subsequent
radical addition of I to styrene (1a) produces carbon-centered
radical II, which could further couple with O2 and copper(I) to
form intermediate IV.12 Finally, IV experiences fragmentation to
give the desired product 3a through elimination of [CuOH]+.
Furthermore, the scope of this aerobic dioxygenation of
alkenes was explored, and the results were summarized in
Scheme 4. Aromatic alkenes showed broad tolerance for both
Furthermore, X-ray absorption near-edge structure (XANES)
spectroscopy was also applied to investigate the reaction between
1a and 2a. The XANES spectrum of the reaction mixture gave a
typical signal for Cu(I) with an edge energy at 8981.6 eV (Figure
3A).11 Cu(II) with the pre-edge at 8977.4 eV was also observed
when the first derivation was calculated (Figure 3B). Moreover,
B
DOI: 10.1021/acs.orglett.5b01223
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Letter
Scheme 3. Proposed Mechanism
Scheme 5. Cobalt-Catalyzed Radical Dioxygenation of 1,1-
Disubstituted Alkenes
a
Scheme 4. Copper-Catalyzed Radical Dioxygenation of
a
Alkenes
a
All reactions were carried out using 1 (0.20 mmol), 2a (0.30 mmol),
and Co(OAc)2·4H2O (0.02 mmol) in toluene (2.0 mL) under O2 for 4
h at 60 °C; isolated yields.
and α-oxo tertiary alcohols were synthesized under mild
conditions. We believe that these results provide useful insight
into abundant metal chemistry and may inspire more efforts
toward further synthetic applications.
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
products. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01223.
a
AUTHOR INFORMATION
Corresponding Author
Unless otherwise specified, all reactions were carried out using 1
■
(0.20 mmol), 2 (0.30 mmol), and CuCl (0.02 mmol) in DMSO (2.0
mL) under O2 for 4 h at 60 °C; isolated yields. NMR yield using
CH2Br2 as internal standard.
b
*E-mail: aiwenlei@whu.edu.cn.
Notes
The authors declare no competing financial interest.
electron-donating substituents (3b−d) and electron-withdraw-
ing substituents (3e−h), furnishing the corresponding α-
oxyketones in good yields.13 The reaction of 2-vinylnapthalene
also proceeded well, giving the product 3i in 61% yield. Notably,
β-methylstyrene was amenable to this protocol as well and
afforded the desired product 3j in 37% yield.14 In addition, other
carbonyl nitroxides were also evaluated. Introduction of a
bromine to the phenyl ring of hydroxamic acid had a negative
effect on the reaction efficiency (3k). It is worth noting that
benzoyl nitroxide, as exemplified by NHPI (N-hydroxyphthali-
mide), was also applicable to this protocol, affording the expected
product (3l) in 74% yield.
Spurred by these encouraging results, we further extended this
protocol to synthesize α-oxo-tertiary alcohols (Scheme 5).
Intriguingly, when Co(OAc)2·4H2O was used to replace the
copper catalyst precursor,15 hydroxamic acid 2a could facilely
react with various 1,1-disubstituted alkenes, furnishing the
corresponding tertiary alcohols 4b−f in 74−92% yields in a
single process.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21025206, 21272180, and 21302148), the Research Fund for the
Doctoral Program of Higher Education of China
(20120141130002), and the Ministry of Science and Technology
of China (2012YQ120060). The Program of Introducing Talents
of Discipline to Universities of China (111 Program) is also
acknowledged. Use of the Advanced Photon Source was
supported by the U.S. Department of Energy, Office of Science,
Office of Basic Energy Sciences, under Contract No. DE-AC02-
06CH11357. MRCAT operations are supported by the Depart-
ment of Energy and the MRCAT member institutions.
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(10) The inductive period might be due to the transformation from
Cu(I) to Cu(II), but other reasons cannot be excluded at current stage.
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(12) According to one of the reviewers, the initial interaction between
Cu(I) and O2 may produce Cu(II) and superoxide radical anion. The
superoxide radical anion could be also possibly coupled with
intermediate II and Cu(II) to give intermediate IV.
(13) Some difunctionalization byproducts generated from one
molecular alkenes reacted with two molecular hydroxamic acid were
detected. In addition, secondary amine generated from the decom-
position of the hydroxamic acid was also detected.
(14) Only a trace amount of the desired product was detected when
(E)-1,2-diphenylethene was employed. For nonaromatic ring sub-
stituted alkenes, as exemplified by acrylic acid butyl ester and
allylbenzene, no desired product was obtained under the standard
conditions.
(15) A 46% yield of 4b was obtained when CuCl (10% mol) was used
as the catalyst precursor.
D
DOI: 10.1021/acs.orglett.5b01223
Org. Lett. XXXX, XXX, XXX−XXX