Selectfluor-mediated highly selective radical dioxygenation of alkenes

Article abstract of DOI:10.1039/c6ra16266e

A practical and simple selectfluor mediated highly selective radical dioxygenation of alkenes was achieved under mild conditions. Various hydroxylamines, such as N-hydroxyphthalimide (NHPI), N-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (NHSI), could react smoothly with alkenes to give β-oxo alcohols and α-oxy ketones in good to moderate yields. The reaction mechanism was primarily investigated and a radical process was proposed.

Full text of DOI:10.1039/c6ra16266e

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Selectfluor-mediated highly selective radical
dioxygenation of alkenes†
Cite this: RSC Adv., 2016, 6, 74917
*
Yunhe Lv, Xin Wang, Hao Cui, Kai Sun, Weiya Pu, Gang Li, Yingtao Wu, Jialin He
and Xiaoran Ren
Received 23rd June 2016
Accepted 2nd August 2016
DOI: 10.1039/c6ra16266e
www.rsc.org/advances
A practical and simple selectfluor mediated highly selective radical used as radical precursors for dioxygenation of alkenes in the
dioxygenation of alkenes was achieved under mild conditions. Various works of Alexanian8 and Lei et al.9 As part of our continuing
hydroxylamines, such as N-hydroxyphthalimide (NHPI), N-hydroxy- interest in employing efficient O-centered radical precursors,
benzotriazole (HOBt) and N-hydroxysuccinimide (NHSI), could react such as NHPI, N-hydroxybenzotriazole (HOBt), N-hydroxy-
smoothly with alkenes to give b-oxo alcohols and a-oxy ketones in succinimide (NHSI) and hydroxamic acid derivatives, for the
good to moderate yields. The reaction mechanism was primarily construction of a C–O bond directly from a C–H bond,10 we
investigated and a radical process was proposed.
present herein our recent progress in selectuor-mediated11
highly selective radical dioxygenation of alkenes, in which
versatile b-oxo alcohols and a-oxy ketones can be synthesized in
a single process (Scheme 1).
Alkenes are the most ubiquitous prochiral functional groups,
and direct difunctionalization of alkenes (whereby two func-
tional groups are added to the same double bond) has attracted
considerable attention in organic synthesis.1 Following the
pioneering work of Sharpless and co-workers,2 metal-free as
well as transition-metal-catalyzed difunctionalization of
alkenes, such as dioxygenation,3 aminooxygenation, diamina-
tion, aminohalogenation, uoroamination, azidooxygenation
and carboamination have been intensively studied.4 Among
which, the selective and sustainable dioxygenation of alkenes is
a valuable synthetic tool for the preparation of 1,2-diols, a-
hydroxyketones, and 1,2-dicarbonyl compounds, which have
high utility in organic synthesis.5 Although there have been
signicant developments in this area in recent decades, the
development of selective dioxygenation reactions remains
challenging. For example, current methods suffer from the use
of toxic and/or expensive transition metals or require dia-
lkylperoxides as initiators.
The initial screening studies were carried out using styrene
(1a) and N-hydroxybenzotriazole (2a, HOBt) as model
substrates. As shown in Table 1, use of FeCl2 as a catalyst and
selectuor as oxidant at room temperature for 12 h in MeCN
produced the desired product 3a in 47% yield together with the
corresponding products 4a (entry 1). The solvent was found to
have a signicant inuence on the reaction efficiency. The
results showed that DCE is a highly effective solvent, affording
the product 3a with the highest isolated yield (Table 1, entry 2–
4). Surprisingly, control experiment in the absence of Fe catalyst
signicantly improved the yield of 3a to 93% yield with high
N-Hydroxyphthalimide (NHPI) is not only a cheap, nontoxic
catalyst for C–H bond functionalization by using an in situ
generated phthalimide N-oxyl (PINO) radical, but also
a precursor of oxime ethers.6 Recently, Punniyamurthy,7a
Woerpel,7b Liang,7c and Tang7d independently reported
transition-metal catalysed oxidation of alkenes using molecular
oxygen and NHPI. Similarly hydroxamic acid derivatives are also
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang,
455000, China. E-mail: lvyunhe0217@163.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra16266e
Scheme 1 Direct dioxygenation of alkenes using hydroxylamines.
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Table 1 Optimization of the reaction conditionsa
Table 2 Selective synthesis of b-oxo alcohols 3a,b
Yieldb (%)
Entry Oxidant
Catalyst
Additive
Solvent 3a
4a
1
2
3
4
5
6
7
8
Selectuor FeCl2
Selectuor FeCl2
Selectuor FeCl2
Selectuor FeCl2
—
—
—
—
—
—
—
—
—
—
—
CH3CN 47
36
Trace
15
Trace
0
0
DCE
DMF
85
26
CH2Cl2 10
Selectuor
—
—
FeCl2
—
DCE
DCE
DCE
DCE
DCE
93
0
TBHPc
Trace Trace
Trace Trace
Trace Trace
d
H2O2
—
9
Na2S2O8
—
10
11
12
13e
Selectuor FeCl3
Selectuor Fe(NO3)3
CH3CN 41
CH3CN 34
20
27
36
Selectuor
Selectuor
—
—
Mn(OAc)3 CH3CN 21
PCC
CH3CN Trace 70
a
Reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), oxidant (0.3
mmol), catalyst (0.03 mmol), additive (0.3 mmol), solvent (3.0 mL), at
b
c
room temperature, in air, 12 h. Yield of the isolated product. TBHP
(70% in water). d H2O2 30% in water. e 3 h.
regioselectivity as well as absolute chemoselectivity (Table 1,
entry 5). Notably, an example of a direct transformation from 1a
and 2a to 3a has not been reported until this work. Neither 3a
nor 4a was observed when selectuor was absent (Table 1, entry
6). Selectuor was the most effective oxidant in the process.
Other oxidants such as tert-butylhydroperoxide (TBHP), 30%
H2O2 and Na2S2O8 did not perform well (Table 1, entries 7–9).
To maximize the yields of 4a, different catalysts and additives
were also tested. Instead of FeCl2, the use of some other iron
catalysts such as FeCl3 and Fe(NO3)3 decreased the yields of 4a
dramatically (Table 1, entries 10 and 11). Then several additives
were screened, such as Mn(OAc)3 and pyridinium chlor-
ochromate (PCC), and PCC gave a better result (70%; Table 1,
entries 12 and 13).
With the optimized reaction conditions in hand, the scope of
this highly selective method was investigated. As described in
Table 2, styrenes 1 with different substituents on the aromatic
ring, including electron-donating and electron-withdrawing
groups, can be transformed into the corresponding products 3
in moderate to excellent yields (3a–r). Halo-substituted styrenes
(1b–e, 1g–i) were tolerated in the dioxygenation reaction, and
could be very useful for further transformations. Notably, trans-
anethole was amenable to this protocol as well and afforded the
desired product 3n in 90% yield. 1,1-Disubstituted alkenes such
as 1o–r were also effective to provide 3o–r in 66–90% yields.
With the role of HOBt established in the dioxygenation, we
sought to explore other hydroxylamines that would effect
similar oxidations. The dioxygenation of styrenes using NHPI
also produced b-oxo alcohols in 80–93% yields (3s–y). In all
cases, the reactions proceeded smoothly at room temperature
a
Standard reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), selectuor
(0.3 mmol), DCE (3.0 mL), at room temperature, in air, 12 h. b Yield of
the isolated products.
under very mild reaction conditions, and the desired b-oxo
alcohols (3a–y) were consistently obtained in moderate to
excellent yields with high regioselectivity and excellent chemo-
selectivity (Table 3).
The success of dioxygenation of alkenes encouraged us to
further explore the scope of this protocol. When PCC was used
as additive, a series of a-oxy ketones were obtained in moderate
to good yields (Scheme 3). Halosubstituted styrenes were also
tolerated in this transformation, forming the corresponding a-
oxy ketones 4b–h, 4l, 4o–r and 4u in 38–75% yields. (E)-1,2-
Diphenylethene can produce the desired 4w in 45% yield. In
addition, starting from NHSI, the corresponding product 4x
could be obtained in 54% yields.
Several control experiments were performed to probe the
reaction mechanism. When the radical scavenger 2,2,6,6-tetra-
methylpiperidine N-oxide (TEMPO, 2.0 equiv.) was added to the
reaction of styrene 1a under the optimal condition, aer 12 h,
a TEMPO-captured product 5 was isolated (69%) and only
a trace amount of 3a was detected (Scheme 2a). In addition,
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Table 3 Selective synthesis of a-oxy ketones 4a,b
Scheme 2 Mechanistic experiments.
a
Standard reaction conditions: 1 (0.36 mmol), 2 (0.3 mmol), selectuor
(0.3 mmol), PCC (0.3 mmol), CH3CN (3.0 mL), at room temperature, in
b
air, 3 h. Yield of the isolated products.
Scheme 3 Proposed mechanism.
adding
a radical inhibitor 2,6-ditert-butyl-4-methylphenol
(BHT) to the reaction system, the formation of the dioxygena-
tion product was also suppressed. The results indicates that
a radical addition mechanism was involved in this trans-
formation. Furthermore, the reaction of 1a, 2a and morpholine
did not result in the formation of 6 (Scheme 2b). When aniline
was introduced into the model reaction mixture, no oxoami-
nation product 7 was observed (Scheme 2c). The above results
indicate that the benzylic carbocation was not involved in this
dioxygenation process. It is notable that no reaction occurred
under N2 and the substrates 1a and 2a were completely recov-
ered (Scheme 2d). To gain insight in the reaction pathway, the
model reaction between 1a and 2a using H218O was conducted
Subsequently, an intermolecular hydrogen abstraction process
occurs between NHPI and B, delivering NIPO radical and
intermediate C. Finally, the intermediate C can be further
transformed into the desired product 3a under acid condi-
tions.14 When PCC was used as additive, the b-oxo alcohols 3a
can be further oxidized to give the a-oxy ketones 4a (see ESI†).
In summary, we have reported a novel selectuor mediated
operationally simple method for selective radical dioxygenation
of alkenes. Various styrenes and a diverse range of hydroxyl-
amines such as NHPI, HOBt and NHSI were efficient. The mild
reaction conditions, broad substrate scope and high chemo-
selectivity and regioselectivity would make this process attractive.
Further investigations to gain a detailed mechanistic under-
standing of this reaction and apply this strategy in other
difunctionalization reactions of alkenes are currently in progress.
18
and no O-labeled product 3a0 was generated, indicating the
oxygen source may be O2 and not H2O (Scheme 2e).
Based on the experimental results and literature prece-
dent,7–10,12 a possible mechanism was proposed in Scheme 3.
Initially, selectuor reacts with NHPI to generate NIPO radical.
Then, radical addition of NIPO radical to styrene affords
carbon-centered radical A, which would further react quickly
with dioxygen and be transformed into peroxyl radical B.13
Acknowledgements
We gratefully acknowledge the Science & Technology Founda-
tion of Henan Province, the Foundation of Henan Educational
This journal is © The Royal Society of Chemistry 2016
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Committee (15A150029), the open project of Jilin Province Key
Laboratory of Organic Functional Molecular Design & Synthesis
(130028651) and AYNU-KP-A04 for nancial support.
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