Electrochemically Tuned Oxidative [4+2] Annulation and Dioxygenation of Olefins with Hydroxamic Acids

Article abstract of DOI:10.1002/anie.202012209

This work represents the first [4+2] annulation of hydroxamic acids with olefins for the synthesis of benzo[c][1,2]oxazines scaffold via anode-selective electrochemical oxidation. This protocol features mild conditions, is oxidant free, shows high regioselectivity and stereoselectivity, broad substrate scope of both alkenes and hydroxamic acids, and is compatible with terpenes, peptides, and steroids. Significantly, the dioxygenation of olefins employing hydroxamic acid is also successfully achieved by switching the anode material under the same reaction conditions. The study not only reveals a new reactivity of hydroxamic acids and its first application in electrosynthesis but also provides a successful example of anode material-tuned product selectivity.

Full text of DOI:10.1002/anie.202012209

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Accepted Article
Title: Electrochemically Tuned Oxidative [4+2] Annulation and
Dioxygenation of Olefins with Hydroxamic Acids
Authors: Bang-Yi Wei, Dong-Tai Xie, Sheng-Qiang Lai, Yu Jiang, Hong
Fu, Dian Wei, and Bing Han
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10.1002/anie.202012209
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RESEARCH ARTICLE
Electrochemically Tuned Oxidative [4+2] Annulation and
Dioxygenation of Olefins with Hydroxamic Acids
Bang-Yi Wei,† Dong-Tai Xie,† Sheng-Qiang Lai, Yu Jiang, Hong Fu, Dian Wei, and Bing Han*
Abstract: This work represents the first [4+2] annulation of hydrox-
amic acids with olefins for the synthesis of benzo[c][1,2]oxazines
scaffold via anode-selective electrochemical oxidation. This protocol
features mild conditions, oxidant free, high regioselectivity and ste-
reoselectivity, broad substrates scope of both alkenes and hydrox-
amic acids, and is compatible with terpenes, peptides as well as
steroids. Significantly, the dioxygenation of olefins employing hy-
droxamic acid is also successfully achieved by switching the anode
material under the same reaction conditions. The study not only
reveals a new reactivity of hydroxamic acids and its first application
in electrosynthesis but also provides a successful example of anode
material-tuned product selectivity.
Introduction
1,2-Oxazinane and benzo[c][1,2]oxazine structural motifs[1] as
one of important N-O heterocycles constitute the core scaffold of
natural products and drugs; selected natural products and drugs
containing such moieties are depicted in Figure 1.[2] On the other
hand, the reductive cleavage of N-O bond of such rings provides
a facile method access to important synthon δ-alkamine.[3] Thus,
the efficient synthesis of 1,2-oxazinane and benzo[c][1,2]oxazine
has attracted much attention from organic chemists and phar-
macologists.[1,4] Among them, taking advantage of Diels-Alder
reaction between nitroso hydrocarbons and dienes has become
a convenient and powerful method to gain access to 1,2-
oxazinanes[5] (Scheme 1a). However, the synthesis of ben-
Scheme 1. Synthetic strategies toward 3,4-dihydro-1H-benzo[c][1,2]oxazines
and the application development of hydroxamic acids.
zo[c][1,2]oxazine using nitrosobenzenes as 4π donors to react
with olefins has been difficult to achieve.[6] Until very recently,
Liu reported the first nitroso-Povarov reaction of nitrosoben-
zenes and substituted cyclopentadienes using vinylallenes as
Hydroxamic acid, a readily accessible precursor, has proven
the substrates under co-catalysis of gold and silver (Scheme
to be oxidized to amidoxyl radical which not only serves as an
1b).[6b] Although the elegant work has been reported, it still re-
attacking species to add onto olefins, but also acts as a trap to
quires noble metals and structurally special alkenes and does
intercept carbon-centered radicals.[7] For example, Alexanian
not apply to ordinary alkenes such as styrenes. Thus, the devel-
reported a remarkable amidoxyl radical-promoted dioxygenation
opment of practical [4+2] protocol toward benzo[c][1,2]oxazine
of alkenes using hydroxamic acids as the partner and oxygen as
by exploring new counterpart of nitrosobenzene to react with
the oxidant as well as the radical trap (Scheme 1c).[7c] Thereafter,
abundant simple alkenes is urgent demanded.
Qing reported an interesting oxytrifluoromethylation of olefins
utilizing the in situ generated amidoxyl radical as the C-radical
interceptor (Scheme 1c).[7d] In this context, we supposed that the
C-radicals derived from intermolecular addition of amidoxyl
radicals onto olefins can further be oxidized to the corresponding
carbocation under suitable conditions, and the latter experiences
a subsequent intramolecular electrophilic substitution with phe-
nyl moiety of hydroxamic acids would provide benzo[c][1,2]
Figure 1. Representative bioactive natural products and drugs.
oxazines (Scheme 1d). Unfortunately, we are aware of no ex-
ample wherein hydroxamic acids are employed as the 4-atom-
center partner with alkenes in a [4+2] annulation. Such situation
[*]
B.Y. Wei, D.T. Xie, S.Q. Lai, Y. Jiang, H. Fu, D. Wei, Prof. Dr. B. Han
State Key Laboratory of Applied Organic Chemistry, College of
Chemistry and Chemical Engineering, Lanzhou University, Lanzhou,
730000, P. R. China
may be caused by the strong trapping capacity of amidoxyl
radicals to suppress the further oxidation of C-radical as afore-
mentioned. Based on our continuous interest in radical reac-
tion,[8] we report herein a novel reactivity of hydroxamic acids by
its anode material-tuned [4+2] annulation with olefins under mild,
metal-free, and terminal oxidant-free electrochemical oxidative
E-mail: hanb@lzu.edu.cn
[†]
B.Y. Wei and D.T. Xie contributed equally for this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Optimization of the Reaction Conditions.[a]
conditions (Scheme 1d). Consequently, a series of monocyclic,
fused cyclic and bridged cyclic 3,4-dihydro-1H-benzo[c][1,2]
oxazines are efficiently synthesized with excellent regioselectivi-
ty and stereoselectivity. Alternatively, the selective electrochem-
ical dioxygenation of olefins with hydroxamic acids can be also
realized by simple replacing the anode material under the same
reaction conditions (Scheme 1d).
Entry
Variation of
Yield[%][b]
conditions
c1
76
27
37
43
0
d1
0
1
2
none
Electrochemical organic synthesis has been revitalized in re-
cent years because it represents one of environmentally friendly
and sustainable chemistry which has the advantage of terminal
oxidant-free.[9] Although lots of electrochemical oxidative reac-
tions such as difunctionalization,[10] oxidative cycloaddition and
annulation of alkenes[11] as well as C-H oxygenation of al-
kanes[12] have been established, those protocols are focused on
the oxidative initiation of C-centered radicals[13] and N-centered
radicals.[14] The generation of oxygen-centered radicals[15] and it
participated reactions are not appreciated it deserved, especially
in intermolecular addition reactions. In addition, with the devel-
opment of electrode materials,[16] the use of different kinds of
electrodes also provides the feasibility for the diversity of elec-
trochemical organic synthesis. In this regard, the tactic not only
realizes the first application of hydroxamic acids in organic elec-
trosynthesis,[15a] but also represents the few successful example
of both electrochemical O-radical triggered cascade reaction and
electrode material-tuned product selectivity.[16e,f]
Pt (+) instead of RVC (+)
C cloth (+) instead of RVC (+)
C rod (+) instead of RVC (+)
C felt (+) instead of RVC (+)
Ni (-) instead of Pt (-)
12
10
26
81
0
3
4
5
6
72
65
58
48
7
Cu (-) instead of Pt (-)
DCM/HFIP/MeCN (3.5:0.3:0.2)
MeCN/HFIP (3.5:0.5)
0
8
< 5
15
9
10
11
12
13
14
15
16
DCM/HFIP (3.5:0.5)
71 trace
nBu4NPF4 instead of nBu4NBF4
nBu4NClO4 instead of nBu4NBF4
Et4NBF4 instead of nBu4NBF4
4 mA, 6 h instead of 6 mA, 4 h
8 mA, 3 h instead of 6 mA, 4 h
without current
50
42
46
64
34
0
0
0
0
0
0
0
[a] Reaction conditions: RVC anode (100 PPI, 10 mm × 10 mm × 5 mm), Pt
cathode (10 mm × 10 mm), constant current = 6 mA, a1 (0.3 mmol), b1 (0.6
mmol, 2 equiv.), nBu4NBF4 (0.4 mmol), solvent (DCM/HFIP/MeCN = 3.5
mL/0.4 mL/0.1 mL), undivided cell, Ar, 4 h (3.0 F mol-1). [b] Isolated yields.
DCM = dichloromethane, HFIP = hexafluoroisopropanol.
Results and Discussion
With the conjecture in mind, we commenced the
electrochemical oxidative [4+2] annulation of hydroxamic acid a1
with styrene b1. After a comprehensive optimization of reaction
conditions by change of electrodes, electrolytes, solvents, and
currents, the optimal conditions for [4+2] annulation was
obtained. By employing an undivided cell furnished with a
reticulated vitreous carbon (RVC) anode and a Pt cathode, the
desired [4+2] annulation product c1 was obtained in 76% yield
after a 6 mA constant current electrolysis in mixed solvents of
DCM/HFIP/MeCN (4 mL, volume ratio: 3.5/0.4/0.1) under Ar
atmosphere for 4 hours at room temperature (Table 1, Entry 1).
The anode material was crucial for an efficient [4+2] annulation
of both selectivity and yield. The replacement of RVC anode by
Pt, C rod, and C cloth gave a mixture of c1 accompanied with
the styrene dioxygenated product d1 in a combined yields
between 39% to 69% with a ratio from 1.6:1 to 3.7:1 (Table 1,
Entries 2-4). Significantly, when C felt was used as anode, the
reaction gave d1 as sole product in 81% yield (Table 1, Entry 5).
The change of cathode had little effect on the reaction, both Cu
and Ni cathodes could provide c1 as sole product, despite in a
bit of lower yields (Table 1, Entries 6 and 7). The change of
solvent burden ratio would also reduce the selectivity and yield
of c1 to some extent (Table 1, Entries 8-10). The remarkable
decrease of yield of c1 was observed by use of nBu4NPF6,
nBu4NClO4, and Et4NBF4 instead of nBu4NBF4 (Table 1, Entries
11-13). The increase or decrease of electrolytic current leaded
lower yields of c1, and no reaction took place under the
conditions of without current (Table 1, Entries 14-16).
to hydroxamic acid a1, and the results are illustrated in Scheme
2. 4-Position substituted styrenes bearing either electron-
withdrawing groups such as CF3, CO2Me, F, Cl, Br or electron-
donating groups such as ClCH2, Me, AcO were all well
compatible with this protocol, delivering the desired benzo[c][1,2]
oxazines c2-c9 in good yields. 3-Chlorostyrene was also
transformed smoothly to c10 in 70% yield in the protocol. When
2-Chlorostyrene participated in the reaction, the corresponding
product c11 was generated in 47% yield, exhibiting a slight of
steric effects. For 2,5-dimethyl styrene, this method generated
the corresponding product c12 in 67% yield. Similarly, 1-
naphthyl ethylene was also converted smoothly in the reaction,
affording c13 in 52% yields. Unfortunately, 2-vinylthiophene was
inert in the reaction and the desired [4+2] product c14 was not
obtained. (E)-1-Propenylbenzene and (E)-1,2-diphenylethene
were good candidates for the approach as well, producing
stereospecific trans-product c15 and c16 in good yields.
Introducing cyclic olefins indene and 1,2-dihydro-naphthalene in
this strategy was also successful, as demonstrated in the cases
of c17 and c18, in which the cis-fused bicyclic products were
obtained in 43% and 71% yields, respectively. This protocol
enabled styrene incorporated steroid and triterpene such as
estrone, lithocholic acid, and 18β-glycyrrhetinic acid derivatives
to undergo the [4+2] annulation very well, providing
benzo[c][1,2]oxazine tethered complex products c19-c21 in 65%,
56%, and 45% yields, respectively. Besides activated olefins,
nonactivated norbornene and its derivatives were good partners
with hydroxamic acid as well, giving rise to the merged
polycyclic products c22 and c23 in good yields with
With the optimal conditions established (Table 1, Entry 1), we
began to evaluate the substrates scope of olefins by subjecting
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Scheme 2. Scope of hydroxamic acids. [a] Reaction conditions, see note [a] in Table 1. [b] Isolated yields. [c] The reaction was conducted on 10 mmol scale.
[d] Olefin (5 equiv.) was used. [e] Piv = Pivaloyl. [f] TBS = tert-Butyldimethylsilyl. [g] Phth = Phthalyl.
exclusive cis- and exo-selectivities. In addition, indoles with
different substituents at various positions were also
successfully converted to the desired fused products c24-c29
in excellent yields with exclusive regioselectivity and
stereoselectivity. The structures of c22 and c26 were
confirmed by X-ray single-crystal diffraction. Notably, this
tactic was also suitable for constructing bridged products by
employing bicyclic olefin 1,2,3,4-tetrahydrocyclopenta[b]indole,
as demonstrated in the case of c30. Significantly, bioactive
indole derivatives such as tryptophol, tryptamine, indole
propionic acid, L-tryptophan and its dipeptide L-tryptophanyl-L-
valine were all participated well in the procedure, generating
the corresponding products c31-c35 in good to excellent
yields. In addition, conjugated dienes such as 2,3-dimethyl-
1,3-butadiene and isoprene were also compatible with this
protocol. The former formed c36 in 40% yield and the later
gave a 5:1 mixture of regioisomers of c37 and c37’ in
Scheme 3. Scope of hydroxamic acids. [a] Reaction conditions, see Entry 1
combined yields of 41%.[17] The successfully achievement of
in Table 1. [b] Olefin (5 equiv.) was used. [c] Isolated yields.
gram-scale preparation of c1 and c24 in 56% (1.60 g) and
68% (2.69 g) yields by constant current electrolyzing 10 mmol
of a1 with the corresponding alkenes, respectively, promised
the practicality and availability of this protocol.
After completing the survey of applicability of olefins, we
shift our attention to investigate the scope of hydroxamic acids
combined yield of 71% with a ratio of 1:1. 2-Methoxyl
hydroxamic acid also gave the corresponding product c44 in
50% yield. This protocol also made promise for 2,4-
disubstituted hydroxamic acid, affording the product c45 as a
by matching with norbornene. As shown in Scheme 3,
single isomer. Drugs and natural products such as amantadine,
hydroxamic acids bearing substituents with a variety of
menthol, and estrone tethered hydroxamic acids were also
electronic properties at 4-position on the phenyl moiety were
tolerated well with this tactic, as demonstrated in the cases
all tolerated in the reaction and produced c38-c42 in good
c46-c48 which provide the desired products in good yields.
yields. When 3-methyl hydroxamic acid was involved in the
reaction, positional isomers c43 and c43’ were obtained in a
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Considering that difunctionalization of olefins is an important
way for the conversion of C=C double bond,[10] we also
realized dioxygenation of olefins using hydroxamic acid by
simple switching the anode from RVC to C felt. As shown in
Scheme 4, the dioxygenation of representative olefins
proceeded very well except indole which was unsuitable under
the present conditions, affording products d1-d10 in moderate
to good yields with good stereoselectivity.
Scheme 4. Dioxygenation of representative olefins. [a] Isolated yield. [b]
Reaction conditions, see Entry 5 in Table 1. [c] nBu4NOAc was used as the
electrolyte.
In order to display the versatile usefulness of products, their
several follow-up transformations were conducted (Scheme 5).
Hydrolysis of c22 delivered
e in 85% yield. Reductive
cleavage of N-O bond followed by hydrolysis/intramolecular
transesterification of c22 gave alkene arylhydroxylated product
f and ring expanded product g in 62% and 61% yields,
respectively. Moreover, by similar reductive cleavage of N-O
bond of product d5, the alkene dihydroxylation product h was
obtained in 70% yield.
Figure 2. Mechanism studies. (a) Competition kinetic isotope effect (KIE)
experiments. (b) Cyclic voltammograms of related compounds (10 mM) in
DCM/HFIP/MeCN (volume ratio: 3.5/0.4/0.1) containing 0.1 M nBu4NBF4.
Glassy carbon working electrode, Ag/AgNO3 reference electrode, platinum
wire counter electrode. Scan rate: 100 mV/s. (c) Electron paramagnetic
resonance (EPR) spectra (X band, 9.4 GHz, DCM/HFIP/MeCN, RT) of A):
a1 without electrolysis; B): constant-potential electrolysis of a1 for 5 min; C):
constant-potential electrolysis of a1 and MNP for 15 min; D) constant-
potential electrolysis of a1, b1, and MNP for 30 min; E) constant-potential
electrolysis of a1, b1, and MNP for 80 min. E = +1.32 V vs. Ag/AgNO3. (d)
Constant-potential electrolysis control experiment.
may involve the anodic oxidation of hydroxamic acids (Figure
2a, Eqs. 1-3). Next, cyclic voltammetry (CV) experiments of
hydroxamic acid a1, styrene b1, norbornene b22, and N-
pivaloyl indole b24 were carried out. An obvious oxidation
peak of a1 could be observed at 1.32 V, whereas no
remarkable peak was seen for b1 and b22 within 2 V,
indicating that b1 and b22 cannot be oxidized simultaneously
when a1 is electrochemically oxidized on anode. Obviously,
that peak is caused by the anodic single electron oxidation of
a1 to the corresponding amidoxyl radical. In addition, an
irreversible reductive peak was observed at 0.78 V in CV
experiment of a1 itself, whereas it was disappeared when b1
Scheme 5. Follow-up transformations.
To achieve insights into the reaction mechanism,
competition kinetic isotope effect (KIE) experiments were first
conducted under the standard reaction conditions. The
measured KIE values from the reaction of an equal amount
mixture of hydroxamic acid a1 and deuterated hydroxamic
acid a1-D5 with styrene b1, norbornene b22 and N-pivaloyl
indole b24 were 1.0, 1.08, and 1.17, respectively, suggesting
that the rate determining step of the reaction does not involve
the C-H cleavage of phenyl moiety of hydroxamic acids and
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and b22 were involved in. These phenomena suggested
clearly that amidoxyl radical generated by the anode oxidation
of a1 was intercepted by olefins (Figure 2b, left). Different from
b1 and b22, indole type substrate b24 presented significant
oxidation peak at 1.58 V, suggesting that a1 and b24 could be
simultaneously oxidized on anode in the reaction. Similarly,
the reductive peak of amidoxyl radical was not observed in the
CV experiment of a1 with b24, manifesting that amidoxyl
radical was intercepted by the in situ formed indole radical
cation (Figure 2b, right). Significantly, the generation amidoxyl
radical and its subsequent radical addition onto styrene given
by CV studies can also be verified by electron paramagnetic
resonance (EPR) experiments (Figure 2c). No EPR signal was
obtained when hydroxamic acid a1 was directly tested without
electrolysis, whereas a triplet signal was detected when a1
was constant-potential electrolyzed at +1.32 V vs. Ag/AgNO3
(Figure 2c, A and B). The triplet signal was assigned as the
metastable amidoxyl radical with aN = 8.03 G and g =
2.0058.[18] When a1 and the carbon-centered radical spin trap
2-methyl-2-nitrosopropane (MNP) were electrolyzed under the
same conditions, only amidoxyl radical triple EPR signal was
obtained (Figure 2c, C); however, when styrene b1 was
introduced into in this electrolytic system, the amidoxyl radical
triple signal was dramatically decreased and a new set of
sextuple signals was obtained (Figure 2c, D). Data analysis
indicates that MNP captures a transient C-atom centered
Figure 3. Proposed mechanism.
oxidation of indole and hydroxamic acid takes place
simultaneously and produces the corresponding amidoxyl
radical I and indole cation radical IV. The radical cross-
coupling (RCC) of those two intermediates generates cation
species V which immediately experiences the same IES to
finally give products c24-c35 (Figure 3, right).
radical to produce the metastable aminoxyl radical Rc (aN
=
Conclusion
15.31 G, aHβ = 3.46 G, and g = 2.0060). Apparently, the
transient C-radical was derived from the addition of amidoxyl
radical onto styrene. With the extension of electrolysis time,
the amidoxyl radical triple signal completely disappeared due
to the trapping of styrene and finally converted to the sextuple
signal of Rc (Figure 2c, E). Notably, bulk electrolysis of a1 and
b1 at the same constant-potential for 4 hours produced the
[4+2] product c1 in 35% yield accompanied with the styrene
dioxygenized product d1 in 20%. This result completely proves
that the formation of c1 and d1 both undergo the initiation of
amidoxyl radical and its radical addition onto styrene; the
formed C-radical further experiences intramolecular cyclization
on phenyl moiety/intermolecular trapping by another amidoxyl
radical would provide the corresponding c1 and d1,
respectively. Such conclusions obtained from constant voltage
electrolysis control reaction are consistent with those obtained
from CV and EPR experiments.
Based on literatures[10g-i] and our observations, the plausible
mechanisms for anode selective [4+2] annulation and alkene
dioxygenation are postulated as shown in Figure 3. Anode
single electron oxidation of hydroxamic acid and subsequent
deprotonation produces amidoxyl radical I. The interception of
radical I by olefins yields C-radical II. Further oxidation of the
latter on anode provides the corresponding carbocation III
which is then undergoes intramolecular electrophilic
substitution (IES) to give annulation products c1-c23 and c36-
c48 (Figure 3, left). On the other hand, C-radical II is trapped
In summary, we have exploited a novel and facile tactic for
the switchable synthesis of 3,4-dihydro-1H-benzo[c][1,2]
oxazines and dioxygenated olefins via anode material-tuned
selective electrochemical oxidative [4+2] annulation/
dioxygenation of olefins with hydroxamic acids for the first time.
The synthetic practicability of this strategy has been
demonstrated by the regiospecific and stereoselective
production of diverse dioxygenated alkenes and mono, fused
cyclic and bridged cyclic 3,4-dihydro-1H-benzo[c][1,2]oxazines
as well as by the compatibility with terpenes, peptides and
steroids. This terminal oxidant-free protocol not only broadens
the new application of hydroxamic acids in synthetic chemistry,
but also represents the few successful example of
electrochemical triggered O-radical cascade reaction and
anode-selective switchable synthetic method. Further research
is under way in our laboratory to use hydroxamic acid as a
precursor of oxygen free radical for new synthesis purposes.
Acknowledgments
We thank the National Natural Science Foundation of China
(Nos. 21873041, 21632001, and 21422205) and the “111”
project for financial support. We also thank Prof. Bo Zhou for
helpful discussion and proofreading of the first version of
manuscript.
by another molecular amidoxyl radical
I finally to give
dioxygenated product d when carbon felt is used as the anode
(Figure 3, left, in dotted box). One possible reason for such
anodic selectivity is that the C-radical is more inclined to
further oxidize to carbocation on an RVC electrode than on a
C felt electrode. For indole type substrate, since its oxidation
potential is similar to that of hydroxamic acid, the anode
Keywords: anode-selective electrosynthesis • annulation •
dehydrogenation • heterocycles • oxygen-centred radicals
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This article is protected by copyright. All rights reserved.

10.1002/anie.202012209
Angewandte Chemie International Edition
RESEARCH ARTICLE
annulation. However, allyl benzene gave mixed products which were
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This article is protected by copyright. All rights reserved.

10.1002/anie.202012209
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
Bang-Yi Wei, Dong-Tai Xie, Sheng-
Qiang Lai, Yu Jiang, Hong Fu, Dian
Wei, and Bing Han*
Page No. – Page No.
Electrochemically Tuned Oxidative
[4+2] Annulation and Dioxygenation
of Olefins with Hydroxamic Acids
This work represents the first [4+2] annulation of hydroxamic acids with olefins for
the synthesis of benzo[c][1,2]oxazines scaffold via anode-selective electrochemical
oxidation. Significantly, the dioxygenation of olefins employing hydroxamic acid is
also successfully achieved by simple switching the anode material under the same
reaction conditions. The study not only reveals a new reactivity of hydroxamic acids
and its first application in electrosynthesis but also provides a successful example
of anode material-tuned product selectivity.
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