Synthesis of Isoxazolines and Oxazines by Electrochemical Intermolecular [2 + 1 + n] Annulation: Diazo Compounds Act as Radical Acceptors

Article abstract of DOI:10.1021/acs.orglett.9b03306

Reported herein is an unprecedented synthesis of isoxazolines and oxazines through electrochemical intermolecular annulation of alkenes with tert-butyl nitrite, in which diazo compounds serve as radical acceptors. Notably, [2 + 1 + 2] and [2 + 1 + 3] annulations occur when styrenes and allylbenzenes are used as substrates, respectively. The latter reaction undergoes group migration to form more stable radical, manifesting radical route instead of conventional 1,3-dipolar cycloaddition occurs. Moreover, scale-up experiments suggest the potential application value of these transformations in industry.

Full text of DOI:10.1021/acs.orglett.9b03306

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Isoxazolines and Oxazines by Electrochemical
Intermolecular [2 + 1 + n] Annulation: Diazo Compounds Act as
Radical Acceptors
Mingteng Xiong,† Xiao Liang,† Zhan Gao,† Aiwen Lei,*,‡ and Yuanjiang Pan*,†
†Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, P. R. China
‡The Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R.
China
S
* Supporting Information
ABSTRACT: Reported herein is an unprecedented synthesis
of isoxazolines and oxazines through electrochemical inter-
molecular annulation of alkenes with tert-butyl nitrite, in
which diazo compounds serve as radical acceptors. Notably,
[2 + 1 + 2] and [2 + 1 + 3] annulations occur when styrenes
and allylbenzenes are used as substrates, respectively. The
latter reaction undergoes group migration to form more stable
radical, manifesting radical route instead of conventional 1,3-
dipolar cycloaddition occurs. Moreover, scale-up experiments
suggest the potential application value of these transformations in industry.
of dinitrogen to achieve a multicomponent series reaction
(Scheme 1c).4 However, there only exist several reports on
such research topics, probably because traditional conditions
for generating free radicals, such as transition metals and high
temperature as well as stoichiometric amounts of oxidants,
easily cause the decomposition of diazo compounds, excluding
the radical process of diazo compounds to a large extent.
Therefore, it is imperative to develop a mild and green method
achieving diazo-involved radical tandem reaction to discover
more unknown reactions.
Organic electrosynthesis, regarded as an eco-friendly and
mild process in which conventional toxic or dangerous
oxidants and reductants could be replaced by electrons,
thereby avoiding many side reactions and byproducts to
acquire the highest reaction efficiency, has been experiencing a
rebirth over the past decades.5 Recently, explosive literature on
electricity-induced free radical reactions has been continuously
reported.6 Given the aforementioned consideration, we try to
develop an electrochemical strategy to merge free radicals with
diazo compounds in a one-pot reaction under mild and metal-
free conditions, achieving intermolecular domino reactions.
Nitrogenous heterocycles, such as isoxazolines and 5,6-
dihydro-4H-1,2-oxazines, the important heterocyclic com-
pounds which have been widely found in pharmaceuticals
and natural products, have attracted much attention over the
past decades, and enormous efforts have been devoted to
exploring the preparation of these structural motifs.7 In
general, current synthetic methods of isoxazolines include
iazo compounds, valuable reagents for chemists, have
1
Dbeen extensively studied in organic synthesis.
Un-
doubtedly, transition-metal-involved reactions of diazo com-
pounds that afford highly active metal carbene species have
occupied the predominant position in recent years (Scheme
1a).2 On the other hand, diazo compounds, serving as
amphiphilic reagents to react with both nucleophiles and
electrophiles, have also been widely used as reactants in
multicomponent reactions (Scheme 1b).3 Recently, it has been
reported that diazo compounds could also serve as good
radical acceptors and form another free radical via the release
Scheme 1. Reaction Types of Diazo Compounds
Received: September 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03306
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Letter
a
1,3-dipolar cycloaddition of nitrile oxide intermediates to 1,2-
dipoles8 (Scheme 2a) and intramolecular free radical addition
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthetic Strategies of Isoxazolines and Oxazines
b
entry
variation from the standard conditions
none
yield (%)
1
2
3
4
78
75
75
65
5 mA instead of 10 mA, 120 min
15 mA omstead of 10 mA, 40 min
n
nBu4NPF6 instead of Bu4NBF4
c
n
5
nBu4NOAc instead of Bu4NBF4
N.D.
6
without HFIP
63
7
adding HOAc as additive
77
8
9
adding K2CO3 as additive
DMF, CH3CN, DCE instead of DCM
0 °C instead of r.t. (20−25 °C)
50 °C instead of r.t. (20−25 °C)
C (+) | Ni (−) instead of C (+) | Pt (−)
Pt (+) | Pt (−) instead of C (+) | Pt (−)
under air
72
10−56
66
69
71
63
58
N.D.
10
11
12
13
14
15
without electricity
a
Reaction conditions: graphite rod anode (ϕ 6 mm), Pt plate cathode
(15 mm × 15 mm × 0.3 mm), constant current = 10 mA, 1a (0.3
mmol), 2a (0.6 mmol), tBuONO (0.9 mmol), nBu4NBF4 (0.6 mmol),
HFIP (1.2 mmol), DCM (10 mL), rt, 60 min, undivided cell, N2,
of oximes9 (Scheme 2b). In contrast, its congener 5,6-dihydro-
4H-1,2-oxazines have hitherto received scant attention due to
lack of convenient and efficient synthetic methods which
usually involve intermolecular [4 + 2] cyclization or intra-
molecular electrophilic cyclizaion (Scheme 2c).10 In recent
years, tert-butyl nitrite (tBuONO) has been reported as a good
nitroxide donor in the literature.11 Based on our interest in
electrochemical annulation of alkenes,12 herein, we attempt to
achieve the synthesis of isoxazoline and 5,6-dihydro-4H-1,2-
oxazine derivatives through diazo-involved electrochemical
b
isolated yield. Determined by GC analysis by using diphenyl as
c
internal standard. N.D. = Not Detected.
explored in Scheme 3. A variety of para-substituted styrenes,
including alkyl, alkoxyl, aryl, halo, trifluoromethyl, and nitro-
substituted styrenes, were smoothly converted to the
corresponding products 3a−3j in considerable yields. Similarly,
ortho- and meta-substituted styrenes were also compatible with
the reaction conditions, forming the target products 3k−3n in
moderate yields. Moreover, the desired product 3o could be
acquired from α-methylstyrene in 50% isolated yield. Mean-
while, vinyl-naphthalene derivatives were also suitable
substrates in this transformation, furnishing the naphthyl-
substituted isoxazoline products 3p and 3q in moderate yields.
Additionally, steric hindrance of substituted groups was also
taken into consideration, and certain multisubstituted styrenes,
such as 2,4,6-trimethylstyrene and 2,6-dichlorostyrene, could
deliver smoothly the corresponding isoxazoline products 3r
and 3s in 52% and 50% yields, respectively. As is known to all,
it is extremely difficult to achieve the difunctionalization of
aliphatic alkenes under metal-free conditions in the electro-
synthesis field,14 perhaps because of the high conversion
energy barrier from alkyl radical to alkyl cation. To our delight,
aliphatic alkenes, including gem-disubstituted alkenes, showed
poor reactivity but moderate compatibility under the similar
conditions, leading to the corresponding isoxazolines 3t−3w.
However, the method was limited to terminal olefins. As
expected, other diazo compounds except diazo amides were
also well-tolerated and transformed smoothly to the corre-
sponding products 3x−3z.
t
tandem annulation reaction of alkenes with BuONO.
To realize the proposed but reasonable transformation, we
t
chose BuONO, ethyl diazoacetate (EDA) 1a, and styrene 2a
as the model substrates to optimize the reaction conditions. To
our delight, the desired product 3a was formed in 78% GC
yield under the standard conditions (Table 1, entry 1).
Obviously, both decreasing and increasing the current had the
negligible impact on the transformation (entries 2−3). After
screening a series of electrolytes, we found that some
n
electrolytes like BuNPF6 went against the reaction and even
n
prevented the transformation, such as BuNOAc (entries 4−
5). Notably, a declining reaction yield, 63%, was obtained
when hexafluoroisopropanol (HFIP) was removed from the
reaction system, and we speculated that HFIP might stabilize
the radical intermediates and facilitate the cyclization (entry
6).12,13 Furthermore, adding some acids or bases as additives
could not promote the transformation to some extent (entries
7−8). Thereafter, solvent effect was also investigated in detail,
and other common solvents, such as DMF, CH3CN, and DCE,
led to the disappointing results (entry 9). In addition, the
inferior yields were obtained when rising temperature or
reducing temperature (entries 10−11). Moreover, the slight
decline of yield was acquired when a nickel plate cathode orc a
platinum sheet anode was used (entries 12−13). When the
reaction was performed under air, the yield sharply reduced to
58% (entry 14). Expectedly, no product was detected without
current passing the reaction system (entry 15).
A series of mechanistic studies were carried out to throw
light on the reaction mechanism. First of all, cyclic
voltammetry (CV) experiments were carried out (Figure 1).
t
An obvious reduction peak of BuONO could be observed at
−0.85 V (vs Ag/AgCl), while no obvious reduction peaks of
With the optimal conditions in hand, the substrate scope of
reaction in regard to the diazo compounds 1 and alkenes 2 was
other substrates could be detected in their cyclic voltammo-
t
grams, implying, to a large extent, BuONO could be reduced
B
DOI: 10.1021/acs.orglett.9b03306
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Letter
a
reaction was also executed in a H-type divide cell and the
Scheme 3. Synthesis of Isoxazolines
target product 3a could be detected in 45% GC yield (Scheme
t
4), indicating that BuONO also simultaneously underwent
Scheme 4. Control Experiment
homolytic cleavage to form both a nitroso radical and a tert-
butoxy radical, and the latter species could capture an electron
at cathode to form the tert-butoxy anion.
Based on the aforementioned results and previously
published literature,4 a mechanism was proposed (Scheme
5). Nitroso radical, resulting from both homolysis and
Scheme 5. Proposed Mechanism for Synthesizing
Isoxazolines
a
Reaction conditions: graphite rod anode (ϕ 6 mm), Pt plate cathode
(15 mm × 15 mm × 0.3 mm), constant current = 10 mA, 1a (0.3
mmol), 2a (0.6 mmol), tBuONO (0.9 mmol), nBu4NBF4 (0.6 mmol),
HFIP (1.2 mmol), DCM (10 mL), rt, 60 min, undivided cell, N2,
isolated yield. bReaction conditions: graphite rod anode (ϕ 6 mm), Pt
plate cathode (15 mm × 15 mm × 0.3 mm), constant current = 10
mA, 1a (0.9 mmol), 2a (0.3 mmol), tBuONO (0.9 mmol), nBu4NBF4
(0.15 mmol), HFIP (3.0 equiv), DMF (10 mL), rt, 80 min, undivided
t
heterolysis of BuONO, is intermediately intercepted by
diazo compounds 1 to afford radical species I with the release
of nitrogen. Subsequently, the electrophilic C-radical I adds to
styrene 2a to deliver the benzylic radical II, which is followed
by the oxidation of II at the anode to produce the benzylic
cation III. The latter species can further tautomerize to IV,
which undergoes an intermolecular nucleophilic attack to
liberate the molecular target 3a. At the same time, part of
tBuONO and tert-butoxy radical generated through homolytic
cleavage captured electrons at the cathode to maintain the
electronic conservation.
c
cell, N2, isolated yield. Home-made materials.
To fully verify that the transformation underwent a radical
route during the whole reaction instead of the 1,3-dipolar
cycloaddition process which was achieved by oxidizing
intermediate I to nitrile oxide intermediate 6 at the anode
(Scheme 6, step i).15 According to the aforementioned
proposed mechanism, it was reasonable to speculate whether
group migration would occur to form the more stable benzyl
radical VI from alkyl radical V when allylbenzene derivatives 4
were used as substrates instead of styrenes 3, achieving
electrochemical intermolecular [2 + 1 + 3] annulation for the
synthesis of 5,6-dihydro-4H-1,2-oxazines (Scheme 6, step ii).
With this idea in mind, the optimal conditions were
determined after a series of condition screening processes
when allylbenzene 4a was used as a substrate, affording the 5,6-
dihydro-4H-1,2-oxazine 5a in moderate isolated yield via a
Figure 1. CV experiments.
by capturing an electron at cathode and undergo heterolysis to
release an electron-rich nitroso radical and a tert-butoxy anion.
Notably, HFIP could decrease the reduction potential of
tBuONO to −0.78 V (vs Ag/AgCl) and the result could
explain why HFIP could facilitate the transformation. To
further clarify the generation of nitroso radical, the model
C
DOI: 10.1021/acs.orglett.9b03306
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Letter
Scheme 6. Proposed Mechanism for Synthesizing 5,6-
Scheme 8. Gram-Scale Synthesis
Dihydro-4H-1,2-oxazines
hydrogen migration process, and the substrate scope was
shown in Scheme 7. Obviously, para-substituted allylbenzenes,
Buchwald-Hartwig coupling reaction, demonstrating the
potential application of these transformations in the field of
industry and medicine.
a
In summary, we have first merged electrosynthesis with
diazo compounds to achieve intermolecular free radical [2 + 1
Scheme 7. Synthesis of 5,6-Dihydro-4H-1,2-oxazines
t
+ n] annulation of alkenes with BuONO via emplaying diazo
compounds as radical acceptors. Undoubtedly, the first
electrochemical [2 + 1 + 2] annulation is an important
complement to conventional synthetic methods of isoxazoline
derivatives. To rule out 1,3-dipolar cycloaddition process, we
have developed an unprecedented approach for the synthesis
of 5,6-dihydro-4H-1,2-oxazines by electrochemical [2 + 1 + 3]
annulation reactions in which group transfer reactions
occurred to generate a more stable intermediate, suggesting
the logicality and rationality of the proposed mechanism.
Remarkably, adding sacrificial additives and releasing the
inflammable and explosive hydrogen, which seem to be the
only imperfection of the dehydrogenation electrosynthesis, can
be averted in these transformations. In addition, these
reactions might have instructive significance in further studies
about exploring new reactions using diazo compounds as
radical acceptors in organic electrochemistry.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03306.
■
a
Reaction conditions: graphite rod anode (ϕ 6 mm), Pt plate cathode
S
(15 mm × 15 mm × 0.3 mm), constant current = 10 mA, 1 (0.9
mmol), 4 (0.3 mmol), tBuONO (0.9 mmol), nBu4NBF4 (0.15 mmol),
HFIP (3.0 equiv), DMF (10 mL), rt, 80 min, undivided cell, N2,
b
isolated yield. Home-made materials.
Experimental procedures, characterization data, and
copies of H and 13C NMR spectra (PDF)
1
including both electron-donating groups and electron-with-
drawing groups, were compatible with the reaction conditions,
releasing the desired products 5b, 5c, and 5d in moderate
yields. Similarly, some ortho-substituted allylbenzene deriva-
tives also showed suitable reactivity and the corresponding
products 5e and 5f were isolated in 54% and 50% yield,
respectively. Reasonably, 2-vinylnaphthalene was tolerated and
gave the target product 5g in 41% isolated yield. It is worth
mentioning that the desired product 5h could be obtained in
considerable yield under the standard conditions via methyl
group migration. As expected, some similar diazo compounds
were also suitable substrates and the corresponding products,
such as 5i and 5j, could be isolated in passable yields.
To further clarify the potential synthetic application of the
protocols, scale-up experiments were carried out (Scheme 8)
To our delight, the considerable isolated yields 66% and
45% were obtained when the gram-scale experiments were
performed on 5 mmol by employing 4-bromostyrene 2h and 2-
allyltoluene 4e as substrates under the respective standard
conditions, and the target isoxazoline 3h could be further
converted to the novel antituberculosis agent7g via the
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: panyuanjiang@zju.edu.cn.
*E-mail: aiwenlei@whu.edu.cn.
ORCID
Aiwen Lei: 0000-0001-8417-3061
Yuanjiang Pan: 0000-0003-2900-2600
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21520102003 and 21532005) and the
Hubei Province Natural Science Foundation of China
D
DOI: 10.1021/acs.orglett.9b03306
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Letter
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