Metal-Free Autoxidative Nitrooxylation of Alkenyl Oximes with Molecular Oxygen

Article abstract of DOI:10.1002/adsc.201600147

A metal-free aerobic autoxidative nitrooxylation of alkenyl oximes mediated by tert-butyl nitrite is described. Molecular oxygen is used as the oxidizing reagent, avoiding use of organic trapping reagents such as 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMP

Full text of DOI:10.1002/adsc.201600147

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DOI: 10.1002/adsc.201600147
Metal-Free Autoxidative Nitrooxylation of Alkenyl Oximes with
Molecular Oxygen
Xiao-Wei Zhang,a Zu-Feng Xiao,a Yan-Jun Zhuang,a Mei-Mei Wang,a
and Yan-Biao Kanga,*
a
Center of Advanced Nanocatalysis, Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, Peopleꢀs Republic of China
E-mail: ybkang@ustc.edu.cn
Received: February 3, 2016; Revised: April 8, 2016; Published online: June 2, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600147.
Abstract: A metal-free aerobic autoxidative nitro-
oxylation of alkenyl oximes mediated by tert-butyl
nitrite is described. Molecular oxygen is used as the
oxidizing reagent, avoiding use of organic trapping
reagents such as 2,2,6,6-tetramethylpiperidine 1-
oxyl (TEMPO). The desired products were ob-
tained in generally high yields.
(entry 2). Further lowering the temperature to À108C
gave rise to an increase in yield up to 92% (entry 7).
The best yield was obtained when 2 equiv. of t-
BuONO was applied (entry 13). Compared to the
quantitative yield given by pure oxygen, the reaction
Table 1. Reaction conditions.[a]
Keywords: aerobic conditions; alkenyl oximes; tert-
butyl nitrite; metal-free procedure; nitrooxylation
Alkenyl oximes are versatile intermediates in organic
synthesis which have been widely used to synthesize
isoxazolines[1] via different strategies such as transi-
tion metal-catalyzed cyclization reactions.[2] However,
a metal-free strategy has been barely reported so
far.[3,4] One example is using TEMPO (2,2,6,6-tetra-
methylpiperidine 1-oxyl) as the oxygen-containing
trapping reagent to afford dioxygenation products.[3a]
A radical autoxidation reaction has proven to be val-
uable for the use of molecular oxygen as a green oxi-
dant.[5] However, the control of highly reactive radical
Entry
Solvent
Variant
T [oC]
2a [%][b]
1
2
3
4
5
6
7
8
THF or CH3CN
THF
–
–
–
–
–
–
–
–
–
–
–
–
r.t.
0
0
0
0
0[c]
72
53
50
63
trace
92
80
72
84
37
44
98
0
CH3CN
toluene
hexane
CH2Cl2
THF
CH3CN
toluene
hexane
CH2Cl2
CH2ClCH2Cl
THF
0
À10
À10
À10
À10
À10
À10
À10
À10
À10
intermediates is still
a
momentous challenge.[6]
9
Herein, we report an autoxidative cyclization of al-
kenyl oximes under aerobic and metal-free conditions
mediated by t-BuONO, a simple organic NO source
as well as a radical initiator. The use of organic trap-
ping reagents such as TEMPO has been avoided by
using molecular oxygen as the sole oxidizing reagent.
Initially, the reaction conditions were investigated.
As shown in Table 1, the autoxidative nitrooxylation
of 1a to 2a is temperature dependent. When the reac-
tion was carried out in various solvents at room tem-
perature, the only product was 2aa as a dimer
(Table 1, entry 1).[3b] On lowering the temperature to
08C, the major product changed to 2a in 72% yield
10
11
12
13[d]
14[d]
15[d]
–
THF
THF
argon
O2
100
[a]
Reaction conditions: 1a (0.25 mmol), t-BuONO
(1.5 equiv.), solvent (2 mL), air.
Isolated yields.
[b]
[c]
1
Only 2aa was observed by H NMR when THF, CH3CN,
CH2Cl2, CH2ClCH2Cl, toluene, or hexane was used as
solvent.
With 2 equiv. of t-BuONO.
[d]
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Table 2. Reaction scope.[a,b]
Scheme 1. Synthetic applications. Reactions conditions: a)
Zn, CH3COOH, H2O, room temperature, 3 h. b) TBSCl,
imidazole, DCM. c) Me3OBF4, NaHCO3, CH3NO2, room
temperature, 4 h. d) NaBH4, EtOH, À308C. e) [RuCl2(p-
cymene)]2, p-TsOH H2O, K2CO3, H2O, toluene, 1108C, 4.5 h.
under an argon atmosphere gave no conversion of 1a
(entries 14 and 15). Using air as oxygen source, the
conditions in entry 7 were chosen as the standard con-
ditions for the autoxidative nitrooxylation of alkenyl
oximes.
The scope of this autoxidative nitrooxylation was
investigated with alkenyl oximes bearing various sub-
stituents. Generally high yields were obtained. For ex-
ample, the gram-scale synthesis of 2a has been ach-
ieved in 86% yield (1.3 g). Besides, other substrates
bearing different substituted phenyls, naphthyl and
heteroaryls (Table 2) gave the corresponding products
in good to excellent yields (2b–2l). Even a quaternary
carbon center with an a-nitrate could be build up
smoothly via this reaction (2m). Unfortunately, when
the methyl group was changed to a phenyl group, no
desired product 2ma was obtained. The GC-MS tests
showed that the reaction carried out under an argon
atmosphere gave the same results as that under
oxygen, suggesting that O2 could not be captured by
[a]
Reaction conditions: 1 (0.25 mmol), THF (2 mL), t-
BuONO (0.5 mmol), À108C under open air atmosphere.
[b]
Isolated yields. For details, see the Supporting Informa-
tion.
this stable radical intermediate. With respect to the cursor which is converted to SCN[8] or OH, providing
starting materials bearing aliphatic or cyclic substitu- an easy access to diol 4 or SCN-substituted isoxazo-
ents (Table 2), the corresponding products were ob- line 3 (Scheme 1). Intermediate 5 was cis-specifically
tained in good to high yields (2o–2s). The intermolec- converted to isoxazolidine 6, which was further trans-
ular autoxidative nitrooxylation between a-methyl- formed to 1,3-oxazinane 7 in excellent yield via our
styrene and acetophenone oxime gave no product 2t. previous method.[9]
The molecular structure of 2c was assigned by X-ray
A radical pathway could probably be involved in
autoxidative nitrooxylation of alkenyl oximes. The re-
crystallography.[7]
This synthetically useful reaction has been applied action of 1a was completely inhibited in the trapping
in the synthesis of synthons or intermediates experiments, affording the TEMPO-trapping product
(Table 1). The nitrooxy ester group is a versatile pre- 2ab in 62% yield [Scheme 2, Eq. (1)]. On the contra-
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primary radical B. At low temperature, the highly
active radical B selectively traps O2 instead of NO[3b]
to form the peroxy radical C,[11b] which captures NO
À
to give peroxynitrite D. The O O cleaving rearrange-
ment of D affords the autoxidative cyclization prod-
uct 2.[11]
In conclusion, a t-BuONO-mediated metal-free au-
toxidative nitrooxylation of alkenyl oximes under
aerobic conditions has been developed, in which mo-
lecular oxygen is used as green and clean oxidizing re-
agent to avoid using an organic trapping reagent such
as TEMPO. Nitrooxyisoxazolines were obtained in
generally high yields. This clean and synthetically
useful reaction has been applied in the synthesis of in-
termediates such as diol and 1,3-oxazinane in high
yields.
Scheme 2. Radical trapping experiments.
ry, the reaction in the absence of t-BuONO gave rise Experimental Section
to the recovery of 1a [Eq. (2)], indicating that t-
BuONO acted as a radical initiator as well as the NO Typical Procedure
source. The radical clock experiment of compound 1u
A solution of oxime 1 (0.25 mmol) in THF (2 mL) in a 25-
further confirmed the radical pathway by isolation of
the ring opening product 2ac in 54% yield [Eq. (3)].
A plausible mechanism for this autoxidative nitro-
oxylation of alkenyl oximes is proposed on the basis
of trapping experiments (Scheme 3). The reaction of
oxime 1 and t-BuONO produces radical intermediate
A,[10] followed by a 5-exo-trig cyclization to generate
mL round-bottomed flask equipped with a magnetic stirring
bar was cooled at À108C under an open air atmosphere.
After 20 min, t-BuONO (2.0 equiv.) was added to the flask.
The mixture was stirred at this temperature until the oxime
was consumed completely as monitored by TLC. Then the
mixture was concentrated and the residue was purified by
silica gel column chromatography.
Warning: despite the fact that peroxides have not been
observed in the small scale reactions, special attention must
be paid to the possible existence of explosive peroxides from
the autoxidation of THF.
Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC 21404096, U1463202), the Fundamental Research
Funds for the Central Universities of China (WK2060190022,
WK2060190026, WK3430000001), and Anhui Provincial Nat-
ural Science Foundation (1608085MB24) for financial sup-
port.
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