Synthesis of Spiroisoxazolines via an Oximation/Dearomatization Cascade under Air

Article abstract of DOI:10.1021/acs.orglett.0c01429

A catalytic, transition-metal-free synthesis of spiroisoxazolines is outlined. This protocol provides, for the first time, a direct access to spiroisoxazolines from aryl (thio)ethers or (thio)phenols in one synthetic step via an oximation/dearomatization

Full text of DOI:10.1021/acs.orglett.0c01429

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Letter
Synthesis of Spiroisoxazolines via an Oximation/Dearomatization
Cascade under Air
Dengfeng Chen, Tianyu He, Yuan Huang, Jinyue Luo, Fei Wang, and Shenlin Huang*
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ABSTRACT: A catalytic, transition-metal-free synthesis of
spiroisoxazolines is outlined. This protocol provides, for the first
time, a direct access to spiroisoxazolines from aryl (thio)ethers or
(thio)phenols in one synthetic step via an oximation/dearomatiza-
tion cascade. In this reaction, sodium nitrite plays dual roles: as a
hydroxylamine source and also a precatalyst to promote the aerobic
dearomatization. This methodology features unprecedented substrate scope, high yields, promising scalability, sustainable oxidant,
and mild conditions.
piroisoxazoline motifs are widely found in a variety of
natural products1 and biologically active molecules.2
Figure 1 illustrates a selection of these molecules with broad
often requires multistep to prepare exocyclic methylene
dipolarophiles, especially for accessing spiro-cyclohexadienyl
isoxazoline core in bromotyrosine alkaloids. Alternatively,
oxidative cyclization of phenolic oxime esters provides a
complementary approach to spiroisoxazoline motifs using
stoichiometric oxidants, such as PhI(OAc)2,6c,p PhI-
(OCOCF3)2,6q,r Br2,6u NBS,6e,l Mn(acac)3,6v and Tl-
(OCOCF3)3,6s,t etc. (see Scheme 1a). Nonetheless, these
reactions still suffer from at least one of the following
limitations: the use of corrosive or stoichiometric highly
oxidative reagents, toxic metals, low selectivity, moderate
yields, and limited examples. Furthermore, a general catalytic
S
Scheme 1. Dearomative Spiroisoxazoline Synthesis
Figure 1. Spiroisoxazoline in natural products and drug candidates.
spectrum of biological activities. A wide range of bioactive
bromotyrosine-derived spiroisoxazoline derivatives have been
first isolated from marine sponges. For instance, subereamol-
line A3 exhibits highly antimigratory activity against metastatic
human breast cancer cells, and calafianin4 displays significant
antimicrobial activity. Aside from marine spiroisoxazolines,
four spiroisoxazoline analoguestrans-xanthoisoxazoline A,
cis-xanthoisoxazoline A, and xanthoisoxazolines B and C
have been recently isolated from the terrestrial plant
Xanthoceras sorbifolia.5 Furthermore, synthetic spirocyclic
isoxazoline derivatives are also promising drug candidates.2
For example, SMARt-4202b has been found to revert antibiotic
resistance in Mycobacterium tuberculosis.
Received: April 24, 2020
Not surprisingly, considerable synthetic efforts have been
dedicated to the search for approaches to assemble these
privileged motifs.6 Such specific motifs are typically built via
1,3-dipolar cycloaddition reactions.6b,h However, this strategy
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A

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Letter
a
oxidative oxo-spirocyclization of aryl ethers with good
functional compatibility is highly desirable.
Scheme 3. Scope of (Thiol)Ether Derivatives
Herein, we report a one-pot, efficient synthesis of
spiroisoxazolines via oximation/dearomatization cascade re-
actions under air at room temperature (Scheme 1b). This
cascade provided a novel tool to access spiroisoxazoline
scaffolds through easily accessible dihydrochalcone derivatives
without the requirement for protection/deprotection. Note
that the dearomatization step features a catalytic oxidative
dearomatization of aryl (thio)ethers and thiophenols using air
as the terminal oxidant with water as the byproduct, as
compared with conventional hypervalent iodine-mediated
dearomatization of phenols.7 This cascade protocol can be
performed at room temperature, with broad substrate scope,
high yields, and promising scalability.
a
Reactions were performed on a 0.2 mmol scale, and all yields
represent isolated yields.
Initially, ketone sulfide 1a-SMe,8 was intended to be
converted to 1,2-diketone 2 (Scheme 2). In a preliminary
of 81% and 84%, respectively. Notably, the cascade reaction
can be performed with high efficiency from other alkyl
protected arenols (O-nPr 1a-OnPr, O-iPr 1a-OiPr, and O-Bn
1a-OBn). With O-silyl protected arenols (1a-TMS and 1a-
TIPS), the reactions proceeded smoothly to provide the
corresponding product 3a in high yields.
Scheme 2. Initial Discovery
We next explored the scope with respect to ortho-
methoxynaphthalenes. The variation of substituents R1 in
methoxynaphtalene (Scheme 4) was first examined. Substrates
with para-substituted arenes, including electron-donating and
a
Scheme 4. Scope of ortho-Methoxynaphthalenes
experiment, we assumed that a treatment of naphthyl methyl
thioether 1a-SMe with NaNO2 (3 equiv) and HCl (18 equiv)
would deliver diketone 2 as the expected product.9 To our
surprise, spiroisoxazoline 3a was isolated in 43% yield, which
was further confirmed by single-crystal X-ray diffraction
(XRD) (CCDC No. 1989746). It is reasonable to hypothesize
that oxime A could be formed by the reaction of 1a-SMe with
sodium nitrite and aqueous HCl.10 Subsequent complexation
of S with NO+ would provide the activated sulfide B.11 Finally,
an oxo-cyclization reaction and hydrolysis would afford
spiroisoxazoline 3a.
Inspired by this unexpected result that provides a novel and
concise access to spiroisoxazolines, we decided to explore this
transformation further. First, naphthyl methyl ether 1a was also
found to be compatible in this spirocyclization, giving the same
product 3a. We then optimized the reaction conditions using
naphthyl ether 1a as the model substrate (see Tables S1−S5 in
the Supporting Information). A variety of reaction conditions,
including different amounts of NaNO2, acids, solvents, and
concentrations, were examined. Ultimately, the desired
dearomatization product 3a was obtained in almost-quantita-
tive yield, in the presence of 1.2 equiv of NaNO2 only at room
temperature under air (Scheme 3).
With the optimized cascade conditions in hand, we set about
examining the generality of this metal-free oximation/
dearomatization cascade. As shown in Scheme 3, both
naphthyl methyl thioether 1a-SMe and naphthyl methyl
ether 1a exhibited excellent reactivity under the standard
conditions. The cascade process also extended to free
(thio)arenols 1a-SH and 1a-OH, which provided 3a in yields
a
Reactions were performed on a 0.2 mmol scale, and all yields
represent isolated yields.
B
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electron-withdrawing groups, underwent the desired oxima-
tion/dearomatization with high efficiency to give the
corresponding spiroisoxazolines 3b−3l in 69%−99% yield.
ortho- and meta-Substituents had marginal effect on the
reaction efficiency, giving 3m−3o in excellent yields.
Naphthyl-substituted substrate also engaged in this reaction
to deliver product 3p in excellent yield. Pleasingly, heteroaryl
substituents, such as furyl, thiophenyl, and pyridyl, were also
tolerable, affording 3q−3s in yields of 79%−98%. Substrates
bearing bulky alkyl groups, including cyclohexyl, tert-butyl, and
adamantanyl, readily participated in this reaction, giving 3t−3v
in excellent yields. It is noteworthy that aldehyde group was
also found to be compatible with the present conditions (3w,
87% yield). Furthermore, dehydroabietic acid-derived ketone
substrate exhibited excellent reactivity, leading to the desired
product 3x in 99% yield. Variation of R2 was also plausible,
where alkyl and aryl substituents were readily integrated into
the products (3y and 3z) at the 4-position of the isoxazoline
ring. With additional substituents on the naphthyl ring of
ortho-methoxynaphthalenes, the reactions proceeded smoothly
to afford 3aa−3ac in excellent yields.
is robust and scalable. On a gram scale, spiroisoxazoline 3a was
obtained in 96% yield from substrate 1a in an open-flask
operation. Selective iodination of 3a delivered 4 in excellent
yield, and the vinyl iodide could be potentially further
elaborated.
To gain some insight into the reaction mechanism, several
control experiments were performed, as shown in Scheme 7.
Scheme 7. Control Experiments
Further substrate scope evaluation revealed that the cascade
protocol can be extended to para-methoxyarenes (Scheme 5).
Intermediate 1aa-oxime could be isolated in 47% yield, along
with 23% of spiroisoxazoline 3aa and 30% of starting material
1aa, when the reaction was quenched after 12 h. With 1aa-
oxime as the substrate in the presence of a catalytic amount of
NaNO2 and 3.6 equiv of HCl under air, the reaction afforded
the desired product 3aa in excellent yield, which indicated that
oxime 1aa-oxime might be the reaction intermediate for the
cascade approach. Furthermore, when the reaction of 1aa-
oxime was conducted under a nitrogen atmosphere, the
desired product 3aa was obtained in only 9%, which suggesting
that the dearomatization is a catalytic, aerobic oxidative
process.
a
Scheme 5. Scope of para-Methoxyarenes
Based on the above investigations and previous reports,11,12
a plausible mechanism for the cascade was postulated as
outlined in Scheme 8. Initially, oxime I is produced by
Scheme 8. Proposed Mechanism
a
Reactions were performed on a 0.2 mmol scale, and all yields
represent isolated yields.
Ketones tethered to 1-methoxynaphthalenes via their 4-
position were efficient substrates, to provide 3ad−3af in yields
of 89%−97%. Of particular note, this oximation/dearomatiza-
tion cascade is also amenable to 4-(4-methoxyphenyl)butan-2-
one 1ag. After the oximation of 1ag, the resulting 1ag-oxime
underwent catalytic dearomatization using 20 mol % of
NaNO2, and 1 equiv of HCl in dichloroethane (DCE) under
1 atm O2, delivering the desired spiroisoxazoline 3ag in 29%
overall yield.
The synthetic utility of this protocol was further
demonstrated (see Scheme 6). This one-pot cascade reaction
nitrosation of the methylene adjacent to the carbonyl group in
1a by NO+, generated from NaNO2 and HCl, and subsequent
isomerization. The methoxynaphthalene in I is then oxidized
by NO+ via single-electron-transfer (SET), affording radical
cation II and nitrogen monoxide (NO). Meanwhile, NO+ is
regenerated by the oxidation of NO by O2 in the presence of
HCl.13 Further spirocyclization14 and deprotonation lead to
radical III, which is oxidized by NO+ to furnish oxocarbenium
cation IV. Finally, the desired product 3a is formed upon
hydrolysis with water. In this cascade, NaNO2 acts as a
Scheme 6. Gram-Scale Reaction and Derivatization
C
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bifunctional agent, a hydroxylamine source for the oximation
and a precatalyst for the dearomative cylization.
Innovation Center of Efficient Processing and Utilization of
Forest Resources, College of Chemical Engineering, Nanjing
Forestry University, Nanjing 210037, People’s Republic of
China
Jinyue Luo − Jiangsu Provincial Key Lab for the Chemistry and
Utilization of Agro-Forest Biomass, Jiangsu Key Lab of
Biomass-Based Green Fuels and Chemicals, Jiangsu Co-
Innovation Center of Efficient Processing and Utilization of
Forest Resources, College of Chemical Engineering, Nanjing
Forestry University, Nanjing 210037, People’s Republic of
China
Fei Wang − Jiangsu Provincial Key Lab for the Chemistry and
Utilization of Agro-Forest Biomass, Jiangsu Key Lab of
Biomass-Based Green Fuels and Chemicals, Jiangsu Co-
Innovation Center of Efficient Processing and Utilization of
Forest Resources, College of Chemical Engineering, Nanjing
Forestry University, Nanjing 210037, People’s Republic of
China; orcid.org/0000-0001-6428-5111
In summary, we have developed a facile synthesis of
spiroisoxazolines, wherein various aryl (thio)ethers or (thio)-
phenols can be well-accommodated to construct the spirocyclic
scaffolds through an oximation/dearomatization cascade.
Notably, this cascade approach enables the direct synthesis
of spiroisoxazolines from aryl (thio)ethers in one synthetic
step; neither prior formation of oxime nor deprotection of aryl
(thio)ethers is required. Our preliminary mechanistic experi-
ments suggest that the oxime is involved as the reaction
intermediate and the following dearomatization reaction is
catalyzed by nitrosonium ion, using air as the terminal oxidant
at room temperature. Sodium nitrite functions as both a
hydroxylamine source and a precatalyst in this cascade. Further
utilization of this protocol to the synthesis of spiroisoxazoline
containing natural products and analogues can be anticipated.
ASSOCIATED CONTENT
* Supporting Information
■
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01429
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01429.
Notes
The authors declare no competing financial interest.
Experimental procedures and characterization data
(PDF)
ACKNOWLEDGMENTS
■
Accession Codes
Financial support provided by the Natural Science Foundation
of China (21502094), and the Natural Science Foundation of
the Jiangsu Higher Education Institutions of China (No.
17KJA220003) is warmly acknowledged. We also grateful for
support by the Advanced Analysis and Testing Center of
Nanjing Forestry University. C.D. thanks the Doctorate
Fellowship Foundation of Nanjing Forestry University and
Postgraduate Research & Practice Innovation Program of
Jiangsu Province for support.
CCDC 1989746 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
REFERENCES
■
Shenlin Huang − Jiangsu Provincial Key Lab for the Chemistry
and Utilization of Agro-Forest Biomass, Jiangsu Key Lab of
Biomass-Based Green Fuels and Chemicals, Jiangsu Co-
Innovation Center of Efficient Processing and Utilization of
Forest Resources, College of Chemical Engineering, Nanjing
Forestry University, Nanjing 210037, People’s Republic of
China; orcid.org/0000-0001-7322-6981; Email: shuang@
njfu.edu.cn
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