A novel synthesis of 5-substituted isoxazoles from propargylic amines and N-hydroxyphthalimide

Article abstract of DOI:10.1016/j.tetlet.2018.04.062

A mild and efficient method for the synthesis of 5-substituted isoxazoles through cyclization of propargylic amines with N-hydroxyphthalimide (NHPI) under metal-free conditions was developed.

Full text of DOI:10.1016/j.tetlet.2018.04.062

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
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A novel synthesis of 5-substituted isoxazoles from propargylic amines
and N-hydroxyphthalimide
a,c,
Yicheng Zhang a,b, Wei Chen b, , Xueshun Jia
⇑
⇑
a School of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, PR China
b Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000, PR China
c Department of Chemistry, Shanghai University, Shanghai 200444, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the synthesis of 5-substituted isoxazoles through cyclization of propar-
gylic amines with N-hydroxyphthalimide (NHPI) under metal-free conditions was developed.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 7 March 2018
Revised 17 April 2018
Accepted 23 April 2018
Available online xxxx
Keywords:
Isoxazole
N-hydroxyphthalimide
N-propargylamine
Introduction
substituted isoxazoles through the cyclization of propargylic oxi-
mes enabled by a variety of electrophiles.8a Then Fokin’s group
N-propargylamines are one of the most useful building blocks in
chemical productions and represent as excellent synthetic inter-
mediates for constructing many significant nitrogen-containing
heterocyclic compounds.1 Recently, N-propargylamines have
received considerable attention as radical acceptors in developing
radical initiated cyclization-aromatization cascades to synthesize
3-substituted quinolines.2 Therefore, direct functionalization of
N-propargylamines to introduce these molecules into complex
organic compounds is important for the synthetic chemistry
community.
Isoxazoles and their derivatives are privileged structural motifs,
which have been widely applied in medicinal chemistry, material
science, natural products, and some other fileds.3 In the past dec-
ades, considerable efforts were focused on the synthesis of isoxa-
zoles,4 largely due to the fact that the functionalized isoxazoles
generally exhibit analgesic,5 antinociceptive,6 and anticancer prop-
erties.7 Therefore, a number of strategies for the construction of
isoxazoles backbone has been reported successively, mainly
including cycloaddition of ketoxime dianions or propargylic
oximes8 and [3+2] cycloaddition of alkenes/alkynes with nitrile
oxides.9 For some selected examples, Larock et al. (2005)
first reported an elegant work on the synthesis of numerous highly
described a novel route to 3,4-disubstituted isoxazoles through
transition-metal-catalyzed [3+2] cycloaddition.9a Recently, Reddy
and coworkers developed a general method for the synthesis of
isoxazoles from readily available propargylic ketones using
TMSN3 as an amino surrogate.10 Despite significant achievement
have been made in past years, most of them still necessitates tran-
sition metal catalysts, additives or harsh reaction conditions. Fur-
thermore, it was found that only a handful of work has been
reported in term of 5-substituted isoxazoles synthesis.11 For
instance, Chen and coworkers recently completed a one-pot syn-
thesis of heterocycles from the propargyl amines, otherwise lim-
ited examples for isoxazole were presented therein.12 Thus, the
development of an alternative approach to 5-substituted isoxa-
zoles using readily available precursors is still highly desirable.
On the other hand, it was found that N-hydroxyphthalimide
(NHPI) as a cheap and readily available chemical has been fre-
quently employed as a catalyst for CAH bond functionalization.13
Recently, some studies revealed that stoichiometric amount of
NHPI could be employed for the CAO bond formation in organic
synthesis.14 However, to the best of our knowledge, there is no suc-
cessful example that has been reported regarding the use of NHPI
for building heterocyclic compounds. Herein, we will report a rare
cyclization of N-propargylamines with NHPI at room temperature,
in which NHPI plays an important role (providing key N-O unit) in
constructing isoxazole molecules.
⇑
Corresponding authors at: School of Environmental and Chemical Engineering,
Shanghai University, Shanghai 200444, PR China (X. Jia).
E-mail address: lake688123@163.com (W. Chen).
https://doi.org/10.1016/j.tetlet.2018.04.062
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhang Y., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.062

2
Y. Zhang et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Results and discussion
In our initial experiment, propargylic amines (1a) and N-
Hydroxyphthalimide (NHPI, 2) were chosen as the model sub-
strates to optimize the reaction conditions. To our delight, the
desired product 3a was obtained in a 44% yield when phenyliodine
diacetate was used as the radical initiator in 1,2-dichloroethane
(DCE) at room temperature for 12 h (Table 1, entry 1). The follow-
ing optimization result showed that the oxidant used in this
cyclization dramatically affected the yield of 3a. For example, the
peroxides, such as tert-butyl hydroperoxide (TBHP), di(tert-butyl)
peroxide (DTBP), benzoyl peroxide (BPO), tert-butyl peroxyben-
zoate (TBPB), 3-chloroperbenzoic acid (m-CPBA), and K2S2O8 were
found to be ineffective in promoting the model reaction, respec-
tively (entries 2–7). Control experiments demonstrated that no
product was formed in absence of oxidant (entry 8). Next, we con-
tinued the condition optimization by investigating the effect of sol-
vent. The results indicated that EtOAc was the best reaction
medium, providing 3a in 84% yield under similar reaction condi-
tions. It was found that the use of 1 equiv. of PhI(OAc)2 led to lower
yield of the product 3a. Meanwhile, a comparable yield (82%) was
obtained with 3equiv. of oxidant (entries 17 and 18). Finally, the
optimized conditions were obtained from the screening of both
reaction temperature and time (entry 16, Table 1).
With the optimized reaction conditions in hand, the scope of
the substrates was investigated as shown in Scheme 1. First, the
reaction between the substituted propargylic amines (1) and NHPI
(2) were conducted under standard conditions. As expected, the
transformation for the substrates bearing with substituents at
the para-position of aromatic alkyne moiety proceeded quite
smoothly, affording the desired 5-substituted isoxazoles in good
Table 1
Optimization of the reaction conditions.a
Entry
Oxidant
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
PhI(OAc)2
TBHP
DTBP
BPO
TBPB
m-CPBA
K2S2O8
–
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
THF
MeOH
DCM
1,4-Dioxane
Acetone
Toluene
DMF
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
44
ND
ND
ND
ND
ND
ND
NR
76
61
73
77
46
a
Scheme 1. The scope of N-methyl-N-propargylanilinesa, Reaction conditions: 1
(0.2 mmol), 2 (0.3 mmol), PhI(OAc)2 (1.5 equiv.) in EtOAc (2.0 mL) at rt. under air for
b
12 h. Isolated yield.
8
9
10
11
12
13
14
15
16
17c
18d
19e
20f
yields (3b-3k). In addition, we found that both electron-donating
i
t
groups (Me, Et, Pr, Bu, nBu and MeO) and electron-withdrawing
substituents (NO2, OAc, CO2Me and CO2Et) within propargylamines
were all well tolerated, thus electronic effects had no significant it
on the yields of according products.cts.
52
Trace
Trace
84
50
82
Additionally, the introduction of methyl group at the meta-
position of aromatic ring in alkyne moiety could also react with
NHPI to give the target product 3L, albeit with the slightly lower
yield. Furthermore, the use of substrate bearing with a methyl
group at the ortho-position of aromatic ring resulted into the for-
mation of the products 3m in 62% yield, probably due to the steric
effect. The cyclization reaction the is amenable to some N-methyl-
N-propargylanilines with the halogen groups at the para and meta
position (1n-s), which gave the corresponding products in moder-
ate yields. Interestingly, the employment of propargylanilines
85
81
a
Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), oxidant (1.5 equiv.) in solvent
(2.0 mL) at r.t. under air for 12 h.
b
Isolated yield.
PhI(OAc)2 (1 equiv.) was used.
PhI(OAc)2 (3 equiv.) was used.
At 60 °C.
c
d
e
f
6 h.
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Y. Zhang et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.04.062.
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to the alkynyliodonium salt A provided the intermediate B, which
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Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21472121) and The Department of Education,
Anhui Province (No. KJ2016A881).
Please cite this article in press as: Zhang Y., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.04.062