Synthesis of spiroisoxazolines via TEMPO/NaNO2-catalyzed aerobic oxidative dearomatization

Article abstract of DOI:10.1021/acs.orglett.0c02372

A catalytic, aerobic oxidative dearomatization protocol has been developed for the preparation of spiroisoxazline scaffolds from oximes using TEMPO and NaNO2 as the catalyst and O2 as the sole oxidant. This dearomatization methodology features its mild reaction conditions, good functional group tolerance, and an unprecedented broad substrate scope, encompassing phenols, aryl ethers, thiophenols, aryl sulfides, etc.

Full text of DOI:10.1021/acs.orglett.0c02372

pubs.acs.org/OrgLett
Letter
Synthesis of Spiroisoxazolines via TEMPO/NaNO2‑Catalyzed Aerobic
Oxidative Dearomatization
Dengfeng Chen, Yaming Wang, Xu-Min Cai, Xiaoji Cao, Ping Jiang, Fei Wang, and Shenlin Huang*
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ABSTRACT: A catalytic, aerobic oxidative dearomatization protocol has been developed for the preparation of spiroisoxazline
scaffolds from oximes using TEMPO and NaNO2 as the catalyst and O2 as the sole oxidant. This dearomatization methodology
features its mild reaction conditions, good functional group tolerance, and an unprecedented broad substrate scope, encompassing
phenols, aryl ethers, thiophenols, aryl sulfides, etc.
Scheme 1. Nitrosonium Ion-Catalyzed Dearomatization
he oxidative dearomatization reaction is a powerful
strategy that offers direct access to highly versatile,
T
three-dimensional molecular architectures from planar arenes.1
Its practicality has been further highlighted by extensive
applications in the synthesis of biologically active molecules
and natural products.2 In particularly, phenols have been
frequently used as the substrates in the dearomative process,
because of their wide availability and low price.3 Classically,
these reactions are mediated by hypervalent iodine com-
pounds; however, typically stoichiometric amounts of hyper-
valent iodine reagents4 or other oxidants5 like m-chloroper-
benzoic acid (mCPBA) are required.
One attractive approach to circumvent this limitation is
catalytic aerobic oxidative dearomatization, using ambient
oxygen as the sustainable oxidant.6 Nitrosonium salts, as
inexpensive and green strong single-electron oxidants with
comparable redox potential to hypervalent iodine reagents, are
attracting attention as versatile and mild oxidants for oxidative
cross coupling.7 For instance, Wang et al. disclosed an efficient
sodium nitrite-catalyzed aerobic dearomatization of electron-
rich phenols, generating spirocyclohexadienones (Scheme
1a).8 Despite the poor conversion of the simple phenol
substrates without electron-releasing groups, it provides a
valuable methodology of spirolization−dearomatization. Very
recently, we described an oxidative dearomatization of in-situ-
formed oxime naphthol derivatives via nitrosonium ion
catalysis under air (Scheme 1b).9 However, the reaction only
works well with highly functionalized naphthalene starting
materials, which limits the scope of accessible spiroisoxazoline
products.
important class of phenolic derivatives.10 In addition, phenolic
substrates can also be readily prepared from anisaldehydes or
tyrosine. Thus, these biorenewable aromatics were utilized as
readily accessible precursors for the synthesis of spiroisoxazo-
line motifs, which are commonly found in natural products11
and drug candidates.12 Herein, we report the first TEMPO/
Received: July 16, 2020
In order to overcome these limitations, we set out to develop
a general protocol that would enable catalytic dearomatization
of simple phenolic derivatives. Chalcones and dihydrochal-
cones, which are widely occurring in wood or plants, are an
https://dx.doi.org/10.1021/acs.orglett.0c02372
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
NaNO2-catalyzed aerobic dearomatization of simple phenolics
at room temperature (Scheme 1c).
Table 1. Optimization of the Reaction Conditions
Our initial attempts focused on the catalytic dearomatization
of oxime ketone 1a, which was prepared from inexpensive and
commercially available 4-(4-methoxy-phenyl)-2-butanone
(raspberry ketone methyl ether, which is a component of the
essential oil).13 We were pleased to discover that the desired
spiro-cyclohexadienone isoxazoline 2a was indeed isolated in
8% yield in the presence of NaNO2 (1.2 equiv) and HCl (1.2
equiv). More interestingly, the extra use of a stable radical
scavenger, 2,2,6,6-tetramethylpiperidin-N-oxyl (TEMPO),
proved critical to improve the dearomatization efficiency.
Based on the above preliminary results, a possible reaction
pathway could be proposed as shown in Scheme 2. At first,
b
NaNO2
(equiv)
H2O
yield
(%)
entry
TEMPO
(equiv)
solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
5 mol %
15 mol %
15 mol %
30 mol %
25 mol %
25 mol %
1.1 equiv
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
−
−
−
−
−
DCE
CHCl3
dioxane
THF
MeCN
EtOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
43
0
0
0
0
−
0
30
50
60
70
100
60
60
60
60
60
60
60
46
52
56
34
49
50
84
90
84
89
0
Scheme 2. Proposed Reaction Mechanism
c
16
0.2
−
−
cd
,
17
18
cd
,
0
a
A mixture of oxime (1a, 0.1 mmol), TEMPO, NaNO2, H2O in
solvent (1 mL) was treated with concentrated HCl (1 equiv) at −5
°C, and the reaction was allowed to warm to room temperature for 36
b
c
h. HPLC yield with diphenyl sulfide as the internal standard. Under
d
O2 (1 atm). Without HCl.
stoichiometric amount of TEMPO (Table 1, entries 17 and
18).
ketone oxime 1a is oxidized to form radical cation I by NO+,14
produced in situ from NaNO2 under acidic conditions. The
resulting radical cation I could cyclize and lose a proton to
furnish radical intermediate II. Without any radical capturing,
the intermediate II could easily revert to its previous state,
preventing its further production to the stable spiroisoxazoline.
However, steered by the persistent radical effect,15 the radical
II couples with TEMPO to afford intermediate III. Under
acidic conditions, a fragmentation of enol ether intermediate
III could produce IV and TEMPOH. Meanwhile, both
TEMPO and NO+ could be regenerated by O2, along with
HCl.16 Hydrolysis of IV eventually delivers the final
spiroisoxazoline 2a. Based on this postulated mechanism,
extensive evaluation of various nitrite salts, additives, and
solvents was therefore performed, with the objective of
improving the reaction efficiency (see Table 1).
Using a catalytic amount of TEMPO, and oxime ketone 1a
as the substrate, we first checked the solvent effect, which
revealed that dichloroethane (DCE) was a better choice than
chloroform (CHCl3), dioxane, tetrahydrofuran (THF),
MeCN, and EtOH (Table 1, entries 1−6). The addition of
water further increased the reaction efficiency (Table 1, entries
7−11). As it turned out to accelerate the hydrolysis, 60 equiv
of H2O were found to be optimal (Table 1, entry 9). To our
delight, employing 25 mol % of TEMPO could significantly
improve the yield to 90% (Table 1, entries 12−15).
Furthermore, the amount of NaNO2 could be reduced to 0.2
equiv in the presence of O2 without affecting the reaction
performance (Table 1, entry 16). In contrast, in the absence of
NaNO2 or HCl, no reaction occurred, even with a
With the optimized reaction conditions in hand, we moved
to the reaction scope study (Scheme 3). First, we explored the
scope of various aryl methyl ethers (Scheme 3A). Ketone
oxime 1a proceeded smoothly to afford 2a in 88% isolated
yield. Gratifyingly, 2a could be obtained on a gram scale in
83% yield. The introduction of an additional R1 substituent at
the benzylic position was also tolerated. For example, aerobic
oxidative dearomatization of ketone oxime 1b afforded 2b in
74% yield. The applicability of this dearomatization was further
demonstrated by varying R substituent in ketone oximes,
affording 2c−2r in good to high yields. Aldehyde and ester
functional groups are compatible with our conditions, with 2c
and 2d forming in 82% and 91% yield, respectively. Pleasingly,
various para-substituents on the phenyl ring were tolerated,
regardless of electron-donating or electron-withdrawing
groups. Moreover, the substituents could be at the para
(2g), meta (2h), or ortho (2i) positions. Notably, naphthyl
(2p), 1,3-benzodioxole (2q), and thiophenyl(2r) were also
amenable to this dearomatization to deliver the desired
spiroisoxazolines in high yields. In addition, variation of R2
substituents in oximes was also possible. High yields of 2s−2x
were observed with electron-donating groups such as methoxy
(2s, 2t, 2w, 2x) and methyl (2u), and also electron-
withdrawing groups such as chloro (2v) at different positions.
It is noteworthy that spiroisoxazoline 2x can be prepared
directly from natural product loureirin A with this protocol.
Unfortunately, no desired reaction was observed with phenols
or phenyl ethers bearing strong electron-withdrawing groups
(−CO2Me or NO2), and this protocol did not show any
B
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a
Scheme 3. Scope of Aerobic Oxidative Dearomatization of Oximes
a
A mixture of oxime (1a, 0.2 mmol), TEMPO (25 mol %), NaNO2 (20 mol %), H2O (60 equiv) in solvent (2 mL) was treated with concentrated
HCl (1 equiv) at −5 °C, and the reaction was allowed to warm up to room temperature under O2 (1 atm) for 36 h.
diastereoselective control (see Scheme S1 in the Supporting
Information).
cones directly to spiro-cyclohexadienone isoxazolines (Scheme
4). This one-pot protocol involves (1) oximination of
We next explored the substrate scope of various tyrosine-
derived oximes (Scheme 3B). Substrates bearing methyl (2y),
ethyl (2d), t-butyl (2z), and benzyl (2aa) esters all underwent
the dearomatization smoothly, delivering the corresponding
products in high yields. Note that 2y and 2z were formed in
yields comparable to or higher than that reported with
methods using hypervalent iodine reagents.17 Furthermore,
chloro-substituted tyrosine oxime also effectively directed the
oxidative dearomatization, generating the desired 2ab.
Aside from above aryl methyl ethers and tyrosine derivatives,
(thio)phenols with different protecting groups were also
examined under the standard conditions (Scheme 3C).
Gratifyingly, the methyl protecting group can be replaced
with acetyl (1a-OAc), benzyl (1a-OBn), n-propyl (1a-On-Pr),
and i-propyl (1a-Oi-Pr) groups without a significant adverse
effect on the yield. Not surprisingly, the corresponding phenol
1a-OH underwent the desired dearomatization as well.
Notably, thiophenol 1a-SH and aryl sulfide 1a-SMe readily
participated in this dearomative cyclization to provide the
corresponding spiroisoxazoline 2a in high yields.
Scheme 4. One-Pot Protocol
dihydrochalcone 3 with sodium nitrite and HCl in THF, and
(2) TEMPO/NaNO2-catalyzed aerobic oxidative dearomatiza-
tion in DCE, leading to spiroisoxazoline 2a in 63% overall
yield.
In conclusion, we have established a catalytic, aerobic
oxidative dearomatization protocol for the practical prepara-
tion of spiroisoxazolines, wherein TEMPO and NaNO2 were
used as the catalyst and ambient O2 as the terminal oxidant.
The dearomatization approach features mild conditions, good
functional group tolerance, and an unprecedented broad
substrate scope, encompassing phenols, aryl ethers, thiophe-
nols, and aryl sulfides, etc. Furthermore, the substrates are
easily accessible from simple, widely available aromatic
feedstocks.
To facilitate the utility of this dearomatization, we examined
the viability of a one-pot strategy for converting dihydrochal-
C
https://dx.doi.org/10.1021/acs.orglett.0c02372
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Notes
ASSOCIATED CONTENT
■
The authors declare no competing financial interest.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02372.
ACKNOWLEDGMENTS
■
Financial support provided by the Natural Science Foundation
of China (No. 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.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
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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