In Situ Generation of Nitrile Oxides from NaCl-Oxone Oxidation of Various Aldoximes and Their 1,3-Dipolar Cycloaddition

Article abstract of DOI:10.1021/acs.orglett.8b03829

Reported is a new green protocol for the efficient in situ generation of nitrile oxides through NaCl/Oxone oxidation of aldoximes and their dipolar cycloaddition. The key feature is the use of a green chemistry approach to address the substrate scope of aldoximes: broad scope (aliphatic, aromatic, and alkenyl aldoximes) without production of organic byproducts derived from oxidant and/or catalyst. Importantly, NaCl/Oxone-promoted three-component cycloaddition of aldehyde, hydroxylamine hydrochloride, and alkene was demonstrated to be competent (63-81%).

Full text of DOI:10.1021/acs.orglett.8b03829

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In Situ Generation of Nitrile Oxides from NaCl−Oxone Oxidation of
Various Aldoximes and Their 1,3-Dipolar Cycloaddition
Guodong Zhao,† Lixin Liang,† Chi Ho Ethan Wen,† and Rongbiao Tong*,†,‡
†Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong China
‡HKUST Shenzhen Research Institute, Shenzhen 518057, China
S
* Supporting Information
ABSTRACT: Reported is a new green protocol for the
efficient in situ generation of nitrile oxides through NaCl/
Oxone oxidation of aldoximes and their dipolar cycloaddition.
The key feature is the use of a green chemistry approach to
address the substrate scope of aldoximes: broad scope
(aliphatic, aromatic, and alkenyl aldoximes) without production of organic byproducts derived from oxidant and/or catalyst.
Importantly, NaCl/Oxone-promoted three-component cycloaddition of aldehyde, hydroxylamine hydrochloride, and alkene
was demonstrated to be competent (63−81%).
Scheme 1. Previous Methods and Our Method for
Generation of Nitrile Oxides for [3 + 2]-Cycloaddition
he 1,3-dipolar cycloaddition of nitrile oxides with various
Talkenes and alkynes is a powerful C−C/C−O bond-
forming transformation to deliver five-membered hetero-
cycles,1−5 isoxazolines or isoxazoles, which are versatile
precursors for β-hydroxy carbonyls and γ-amino alcohols in
the chemical synthesis of (non)natural products.6−10 Gen-
eration of the nitrile oxides is critical to this [3 + 2]-
cycloaddition and often achieved by one of two strategies:
dehydration of nitroalkanes11−17 or oxidation of aldoximes18,19
(Scheme 1a). The oxidative process has received much
attention toward methodology development and more
applications in total synthesis of complex molecules presum-
ably because of the readily available aldoximes (condensation
of aldehyde and hydroxylamine), mild and selective oxidation
conditions, and tolerance of various functional groups. Many
oxidants including t-BuOCl, t-BuOI, m-CPBA, ArI(OAc)2,
DMDO, NXS, NaClO, NaBrO2/Bu3SnCl, Chloramine-T,
PhICl2, MnO2 ,and CrO2 (Magtrieve) have been identified
for efficient generation of nitrile oxides from aldoximes.20−31
However, most oxidants either require in-house preparation (t-
BuOI, t-BuOCl, and DMDO) or produce stoichiometric toxic
organic byproducts (NCS, NBS, m-CPBA, and ArI(OAc)2).
From a green chemistry point of view, Oxone (triple salt of
potassium peroxymonosulfate: 2KHSO5−KHSO4−K2SO4) is
an environmentally friendly, bench-stable, nontoxic, inorganic
oxidant and, therefore, should be an ideal oxidant for
aldoximes. Without surprise, Oxone was used as the terminal
oxidant by Yoshimura, Zhdankin, and co-workers for oxidative
cycloaddition of aldoximes and alkenes/alkynes through two
intriguing mechanisms (Scheme 1b and 1c).32,33 One major
limitation of these two Oxone-based approaches is the poor
yield (8%−17%) for the oxidative cycloaddition of aliphatic
aldoximes. To address this limitation, we initiated our study
and herein report our findings that NaCl/Oxone/Na2CO3 is a
green and efficient catalytic system for in situ generation of
both aromatic and aliphatic nitrile oxides for [3 + 2]-
cycloaddition (Scheme 1d). Notably, NMR characterization
of the isolated intermediates (hydroximoyl chloride and nitrile
oxide) suggested that the mechanism was different from those
proposed by Yoshimura and Zhdankin (Scheme 1b,c).
In continuation of our long-term program of green oxidation
through exploitation of Oxone and halide with the ultimate
goal of replacing NXS (or other halogenating agents: Cl2, Br2,
Received: November 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03829
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Letter
t-BuOX, HOX, and others) in organic synthesis,34−37 we were
interested in exploring the replacement of the widely used
NCS (or t-BuOCl) with Oxone/NaCl for the in situ
generation of nitrile oxides from aldoximes (Scheme 2). We
Table 1. Optimization of Catalytic Cycloaddition of
Aliphatic Aldoxime 1a with Aliphatic Alkene 2a
a
Scheme 2. Our Hypothesis of Generation of Nitrile Oxide
through Oxone/NaCl Oxidation of Aldoxime and HCl
Elimination
b
Oxone
base
solvent
yield
entry MX (eq)
(equiv)
(1.5 equiv)
(v/v, 20/1)
(%, 3a)
1
NaCl
(0.1)
1.5
Na2CO3
MeOH/H2O
32
2
3
NaI (0.1)
NaBr
(0.1)
1.5
1.5
Na2CO3
Na2CO3
MeOH/H2O
MeOH/H2O
33
28
4
5
6
KI (0.1)
NaI (0.1)
NaBr
(0.1)
1.5
1.5
1.5
Na2CO3
MeOH/H2O
MeOH/H2O
MeOH/H2O
34
0
0
7
NaCl
(0.1)
NaCl
(0.1)
NaCl
(0.1)
NaCl
(1.1)
NaCl
(1.1)
NaCl
(1.1)
1.5
1.5
1.5
1.5
1.5
1.5
1.1
1.1
1.1
MeOH/H2O
MeOH/H2O
MeOH/H2O
MeOH/H2O
THF/H2O
0
30
25
66
15
77
77
65
46
c
8
NaHCO3
envisioned that aldoxime could be oxidized by Oxone and
NaCl to provide the hydroximoyl chloride, and sodium
carbonate may be used to replace Et3N to effect the
elimination of HCl to generate the nitrile oxide along with
regeneration of NaCl as the catalyst. Obviously, the possible
competitive dichlorination of alkene reported by our group
using Oxone/NaCl37 (in CH2Cl2−H2O) was a concern, and
different reaction conditions might be needed to point the
reactivity toward the generation of nitrile oxides.
9
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
10
11
12
MeCN/H2O
MeCN/H2O
MeCN/H2O
MeCN/H2O
13 NaCl
(0.7)
14
We chose aliphatic aldoxime 1a and aliphatic alkene 2a to
examine our hypothesis (Table 1). Gratifyingly, our initial
attempt was very positive: 32% yield of isoxazoline 3a was
NaBr
(0.7)
NaI (0.7)
15
1
detected by H NMR when the MeOH/H2O solution of 1a
a
Conditions: To a solution of 1a (0.2 mmol) and 2a (0.26 mmol) in
and 2a at rt was treated with Oxone (1.5 equiv), NaCl (0.1
equiv), and Na2CO3 (1.5 equiv) (Table 1, entry 1). Notably,
no alkene dihalogenation was observed. Interestingly, we found
that the use of NaBr, NaI, or KI as the catalyst also delivered
the cycloaddition product 3a with low yields (entries 2−4).
The absence of sodium carbonate resulted in no generation of
nitrile oxide but only hydroximoyl halide (entries 5−7).
Further examination of different bases, solvents, and
stoichiometry (entries 8−13) led us to identify the optimal
conditions for the [3 + 2]-cycloaddition with 77% yield (entry
13). Intriguingly, chloride outperformed the corresponding
bromide and iodide under otherwise identical conditions
(entries 14 and 15).
With the optimized conditions in hand, we set out to
examine the substrate scope of [3 + 2]-cycloaddition of
aliphatic aldoximes with various types of alkenes and alkynes
(Scheme 3). The in situ generated isopropyl nitrile oxide from
isopropyl aldoxime can react with various terminal alkenes to
provide isoxazolines with excellent yields. The regioselectivity
was excellent (5-isomer for terminal alkene) and consistent
with the general regioselectivity trend reported in the
literature.1−5,38 Notably, under these mild reaction conditions,
a variety of functional groups survived, including electrophilic
alkyl bromide (3c and 3d), silyl ether (3e and 3j), lactone
(3g), and alcohol (3k and 3l). The electron-rich alkene (3i),
allyl silane (3h), aromatic alkenes (3n−p), electron-deficient
acrylate (3q−t), acrylonitrile (3u), and enones (3m, 3v,w)38
were excellent substrates for the [3 + 2]-cycloaddition of this
in situ generated aliphatic nitrile oxide. Other aliphatic
aldoximes also reacted efficiently with alkenes to provide the
isoxazolines in excellent overall yields (3x−ae). In addition, the
cycloaddition of the aliphatic aldoxime with alkynes proceeded
the solvents (1.0 mL) at room temperature were added Oxone, metal
b
halide, and base and the reaction mixture was stirred for 12 h. Yield
1
was determined by H NMR of the crude reaction mixture using
c
CH2Br2 as the internal reference. 3.0 eq was added.
smoothly to provide the corresponding isoxazoles in excellent
yield (3af−ai).
Next, we were interested in extending the aliphatic
aldoximes to aromatic aldoximes for the oxidative cyclo-
addition. Gratifyingly, under our optimized standard condition,
all examined aromatic aldoximes regardless of electronic and
steric properties were competent substrates for oxidative
cycloaddition with tert-butyl acrylate (Scheme 4). Notably,
the heteroaromatic aldoximes (3aq−as) could be used under
theses oxidation conditions for 1,3-dipolar cycloaddition, and
we did not observe the oxidation of thiophene, furan, or
pyridine (readily oxidized to be an N-oxide derivative).39,40
Remarkably, conjugate aldoximes could also be employed
under our conditions for the oxidative cycloaddition (3at−av).
It was noted that alkynyl aldoxime was a poor substrate (3aw),
which was the only type of aldoxime examined to give low
yield. Nevertheless, the generality of the aldoxime scope was
indeed remarkable and beyond our initial expectation of
addressing the generation of nitrile oxides from aliphatic
aldoximes.
Finally, we attempted to isolate and characterize the
hypothetic intermediates hydroximoyl chloride and nitrile
oxide in order to shed light on the underlying mechanism
(Scheme 5). Oxidation of isopropyl aldoxime (1a) with Oxone
and NaCl in the absence of sodium carbonate occurred within
2 h to provide isolable hydroximoyl chloride 4a (90% yield),41
B
DOI: 10.1021/acs.orglett.8b03829
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Letter
Scheme 3. Substrate Scope of Oxidative [3 + 2]-
Scheme 4. Oxidative [3 + 2]-Cycloaddition of Conjugate
Aldoximes with tert-Butyl Acrylate
a
Cycloaddition of Aliphatic Aldoximes with Alkenes and
a
Alkynes
a
Conditions: To a solution of 1 (0.46 mmol) and 2r (0.6 mmol) in
MeCN/H2O (20/1, 2.0 mL) at room temperature were added Oxone
(311 mg, 1.1 equiv), NaCl (18.8 mg, 0.7 equiv), and Na2CO3 (73.1
b
mg, 1.5 equiv) for 12 h. NaHCO3 (154.7 mg, 4 equiv) was used
instead of Na2CO3, and the reaction time was 2 h.
Scheme 5. Isolation and Characterization of Hydroximoyl
Chloride and Nitrile Oxide and Our Mechanistic
Hypothesis
a
Conditions: To a solution of 1 (0.46 mmol, 1.0 equiv) and 2 (0.6
mmol, 1.3 equiv) in MeCN/H2O (20/1, 2 mL) at room temperature
were added Oxone (311 mg, 1.1 equiv), NaCl (18.8 mg, 0.7 equiv),
b
and Na2CO3 (73.1 mg, 1.5 equiv) for 12 h. NaHCO3 (154.7 mg, 4.0
equiv) was used instead of Na2CO3, and the reaction time was 2 h.
c
Reaction time was 6 h.
1
which was confirmed by H NMR and then treated with
sodium carbonate and tert-butyl acrylate to afford the
cycloaddition adduct 3r in 82% yield. Similarly, hydroximoyl
chloride 4ap41 could be isolated in 95% yield from the base-
free oxidation of mesityl aldoxime 1ap. Remarkably, upon
treatment of 4ap with sodium carbonate the mesityl nitrile
oxide (5ap)42 was stable enough to be isolated for H NMR
1
spectral analysis and cycloaddition with tert-butyl acrylate.
These findings allowed us to conclude that the oxidation of
aldoximes with Oxone and NaCl provided the key
intermediate hydroximoyl chloride, which upon treatment of
base underwent HCl elimination to generate the nitrile oxide
for the cycloaddition. Therefore, the detailed mechanism was
proposed as depicted in Scheme 3b. Oxidation of chloride with
Oxone would generate the chlorinating species I (Cl2 or
HOCl). Chlorination of the aldoxime might involve inter-
mediate II or III to provide the hydroximoyl chloride IV.
Sodium carbonate as a base would promote the HCl
elimination to generate the nitrile oxide V, along with
regeneration of chloride for Oxone oxidation in the next
catalytic cycle. It is generally well accepted that the 1,3-dipolar
cycloaddition of nitrile oxides with alkenes follows a concerted
pathway to give isoxazolines (V → 3).43
Finally, we decided to examine the possibility of combining
the aldoxime formation and oxidative cycloaddition in a one-
pot sequential manner. Guided by our mechanistic under-
standing, we conceived that NaCl generated as a byproduct in
the condensation of aldehyde (6a or 6an) and hydroxylamine
hydrochloride can be used in the second step (cycloaddition)
C
DOI: 10.1021/acs.orglett.8b03829
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Letter
as the catalyst for Oxone−NaCl oxidative cycloaddition
(Scheme 6), while stoichiometric water from the condensation
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: rtong@ust.hk. Fax: +(852) 23581594. Tel: +(852)
Scheme 6. Three-Component Oxidation Reaction of
Aldehyde, Hydroxylamine Hydrochloride, and Alkene
23587357
ORCID
Rongbiao Tong: 0000-0002-2740-5222
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the Research Grant
Council of Hong Kong (GRF 605113, 16311716, 16303617)
and the National Natural Science Foundation of China (NSFC
21472160 and 21772167).
to aldoxime was beneficial for dissolving the Oxone or at least
tolerated in the second step. To verify our hypothesis, we
carried out the experiment by simply mixing the aldehyde (6a
or 6an), hydroxylamine hydrochloride, Na2CO3, Oxone, and
the alkene (2a or 2r) in CH3CN in one flask, and the mixture
was stirred vigorously for 12 h. To our delight, comparable
high yields (63−81%) were obtained for all three representa-
tive examples (3a, 3r, and 3an). This was truly remarkable
because it was (1) a new three-component reaction that
formed three new bonds, CN, C−C, and C−O, (2) a good
example that a byproduct (NaCl) in the first step was fully
utilized in the second step (one pot) as a catalyst or reagent,
and (3) the greenest and most atom-economic [3 + 2]-
cycloaddition of nitrile oxides with alkenes. It is expected that
other aldehydes and alkenes could be used for this three-
component oxidative cycloaddition with hydroxylamine−HCl.
In summary, we have developed a new green protocol for
efficient in situ generation of nitrile oxides from Oxone/NaCl
oxidation of aldoximes for 1,3-dipolar cycloaddition with
different alkenes and alkynes. The key feature of this new
method is the use of a green chemistry approach to address the
substrate scope: broad scope (aliphatic, aromatic, alkenyl
aldoximes) without generation of organic byproducts. The
simple open-flask operation, low-cost and nontoxic reagents,
and air and moisture insensitivity are of high value and should
attract attention from the synthetic community and find wide
applications in organic synthesis. Finally, we successfully
achieved a new three-component reaction of aldehyde,
hydroxylamine hydrochloride, and alkenes for the synthesis
of isoxazolines by exploiting the hypothetic mechanism with a
green chemistry approach. This three-component oxidative
cycloaddition is expected to have an extensive impact on
application of cycloaddition of nitrile oxides in medicinal and
organic synthesis.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03829.
Experimental details, procedures, and characterization of
all compounds (PDF)
D
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