TEMPO-catalyzed synthesis of 5-substituted isoxazoles from propargylic ketones and TMSN3

Article abstract of DOI:10.1039/c6ra11099a

A novel and efficient TEMPO-catalyzed synthesis of 5-substituted isoxazoles from propargylic ketones and TMSN₃via a radical mechanism process is described. This methodology provides an easy access to a variety of useful 5-substituted isoxazoles

Full text of DOI:10.1039/c6ra11099a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: Y. He, Y. Xie, Y.
Wang, X. Bin, D. Hu, H. Wang and Y. Pan, RSC Adv., 2016, DOI: 10.1039/C6RA11099A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Please do not adjust margins
RSC Advances
Page 1 of 7
View Article Online
DOI: 10.1039/C6RA11099A
RSC Advances
PAPER
TEMPO‐catalyzed Synthesis of 5‐Substituted Isoxazoles
from Propargylic Ketones and TMSN3
Received 00th January 20xx,
Yan He, +a Yu‐yang Xie, +a Ying‐chun Wang,b Xiao‐min Bin,a Da‐chao Hu,a Heng‐Shan Wang*a and
Ying‐Ming Pan*a
A novel and efficient TEMPO‐catalyzed synthesis of 5‐substituted isoxazoles from propargylic ketones and TMSN3 via the
radical mechanism process is described. This methodology provides an easy access to a variety of useful 5‐substituted
isoxazoles from simple and readily available propargylic ketones and TMSN3 in good to excellent yields. A plausible
reaction mechanism for this process is proposed.
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
yielding, only a limited number of methods for the synthesis of 5‐
substituted isoxazoles have been described.10 Forthermore, some of
these methods face the limitation of low atom efficiency, substrate
specificity or forcing conditions. Therefore, the development of new
methods for the regioselective synthesis of 5‐substituted isoxazoles
under mild reaction conditions is still highly desired.
Recently, organocatalysis has attracted considerable
attention and has been significantly developed.11 2,2,6,6‐
tetramethylpiperidine 1‐oxyl (TEMPO), a shelf‐stable radical
species, is the catalyst of choice in industry and has been
widely used for the oxidation of alcohols to carbonyls.12
Notably, TEMPO has been reported as a nonmetal catalyst in
C=C double‐bond cleavage to produce oxo nitriles.13 Herein,
we report a TEMPO catalyzed unsubstituted propargylic
ketones to produce 5‐substituted isoxazoles using a useful
reagent TMSN3 as the nitrogen source (Scheme 1).
Introduction
The isoxazole core, one of the important five‐membered nitrogen
heterocyclic, occupy an important place in organic chemistry1
because of their wide applications in medicinal chemistry,2 material
science,3 biologically active molecules,4 and as intermediates in
organic synthesis.5 For this reason, considerable research efforts
have been focused on the development of novel and efficient
methods for the synthesis of isoxazoles. There are three main
methodologies: the cyclization of ketoxime dianions or propargylic
oximes (Scheme 1, A),6 [3+2] cycloaddition reaction (Scheme 1, B),7
and condensations with hydroxylamine (Scheme 1, C).8 For example,
in 2005, Larock and co‐workers reported the isoxazole products
obtained from cycloisomerizations of propargylic oximes with ICl, I2,
Br2, or PhSeBr.6a Fokin group in 2008 reported that a Ru(II)‐
catalyzed [3+2] cycloaddition of alkynes with nitrile oxides to give
3,4‐disubstituted isoxazoles.7b And In 2014, Liang reported the
synthesis of disubsituted isoxazoles from homopropargylic alcohol,
t‐BuONO, and H2O via condensation with hydroxylamine.8c Very
recently, Reddy et al. reported the direct tandem azidation and
denitrogenative cyclization of internal propargylic ketones with
trimethylsilyl azide as an amino surrogate (Scheme 1, D).9 However,
they did not elaborate their methodology with unsubstituted
propargylic ketones. Although, the poly‐substituted isoxazoles could
be get by these methods which are general, regioselective, and high
a. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal
University, Guilin 541004, People’s Republic of China. E‐mail:
whengshan@163.com, panym2013@hotmail.com
b. College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000,
People’s Republic of China
+These authors contributed equally to this work.
† Electronic Supplementary Information (ESI) available: [general experimental
procedures, and spectral data, NMR spectra, high resolution mass spectra for all
compounds, and X‐ray crystallographic files (CIF) for 2g]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Synthesis of isoxazoles
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 2 of 7
ARTICLE
Journal Name
Table 2 Substrate Scope for the reaction of propargVyileiwc AkretictolenOenslin1e
Results and discussion
a, b
DOI: 10.1039/C6RA11099A
and TMSN3
At the outset of our studies, the reaction of propargylic ketone 1a
with TMSN3 was attempted under different conditions (Table 1).
When the reaction was catalyzed by TEMPO, no desired product
was detected with most of propargylic ketone 1a remained (Table 1,
entry 1). Then, we were glad to find that propargylic ketone 1a was
converted into isoxazole 2a when Mn(OAc)2∙2H2O (15 mol %) was
employed (Table 1, entry 2). We conjectured that the reaction were
carried out in the presence of H2O. Therefore, various catalyst were
subsequently screened in this reaction, such as CuBr, MnO2, MnCl2 ,
MnBr2 and TEMPO (Table 1, entries 3‐7). Among them, TEMPO was
found to be the optimal one and afforded product 2a in 76% yield
(Table 1, entry 7). Subsequently, various solvents examined, DMSO,
toluene, CH2Cl2, 1,4‐dioxane and DMF turned out to give the
product (Table 1, entries 8‐12). To our delight, in CH3OH without
H2O, TEMPO performed well with high effectivity delivering the
product in good yield (78% isolated yield, Table 1, entry 13). CH2Cl2
and 1,4‐dioxane without H2O were tested, we can not get the
desired product (Table 1, entries 14‐15).
Table 1 Optimization of reaction conditions a
Entry
1
Catalyst
TEMPO
Solvent
CH3CN
Yield b (%)
N.R.
2
3c
4c
5c
6c
7c
8c
9c
10c
11c
12
13
14
15
Mn(OAc)2∙2H2O
CuBr
CH3CN
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
DMSO/H2O
toluene/H2O
CH2Cl2/H2O
1,4‐dioxane/H2O
DMF/H2O
55%
N.R.
N.R.
N.R.
63%
76%
40%
47%
71%
74%
69%
78%
N.R.
N.R.
a
Reaction conditions: 1 (0.3 mmol), TMSN3 (0.45 mmol), TEMPO
(15 mol%) in CH3OH (2 mL) under air at room temperature. PPh3
(1.0 equiv.) was added after 12 h and the mixture was stirred for
another 1 h. b Isolated yield of pure product based on 1.
MnO2
MnCl2
MnBr2
With the optimized conditions in hand, the scope of substrates
that could participate in the reaction was next investigated (Table
2). The acetylenic ketones 1a‐1s were either commercially available
or prepared using a known procedure (see ESI). To our delight, aryl‐
alkynyl ketones bearing various substitutes participated well in the
cyclization reaction, gave 5‐substituted isoxazoles 2a‐2j in moderate
to good yields (70‐85%). And the substrate with an electron‐
withdrawing group on the aromatic ring gave better yield than that
of an electron‐donating group on the aromatic ring. The
crystallization of compound 2g from ethanol gave a single crystal
suitable for X‐ray analysis. Figure 1 illustrates the molecular
structure of the 5‐substituted isoxazole 2g. When the aryl group
was substituted in the 2‐, 3‐, and 4‐positions by a CH3 group, the
corresponding isoxazole compound could be synthesized in 76%,
78%, and 77% yield, respectively. Gratifyingly, 5‐(2‐bromo‐5‐
methoxyphenyl)isoxazole (1i) and 5‐(4‐(tert‐butyl)phenyl)isoxazole
(1j) were found to the reaction, providing the desired products 2i
and 2j in 79% and 70% yield, respectively. Fortunately, propargylic
ketones containing heteroaryl units or condensed rings were also
tolerated (2k, 2l and 2m). It should be noted that the reactions with
the alkyl acetylenic ketone, leading to moderate yields of products
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
CH3OH
CH2Cl2
1,4‐dioxane
a Reaction conditions: 1a (0.3 mmol), TMSN3 (0.45 mmol), catalyst
(15 mol%) in solvent (2 mL) at room temperature for 12 h under air.
PPh3 (1.0 equiv.) was added after 12 h and the mixture was stirred
for another 1 h. b Isolated yield of pure product based on 1a. 0.2
c
mL H2O was added.
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 7
RSC Advances
Journal Name
ARTICLE
TMSN3
CH3OH
View Article Online
TMSOCH3
N DOI:+10.1039/C6RA11099A
N3
+
N
N
O
OH
A
B
OTMS
O
O
N
O
O
N
N3
Ph
OH
Ph
N
Ph
Ph
N3
N
N
N N
1
7
5
6
N
O
O
Figure 1 X‐ray Crystal Structure of 5‐substituted isoxazole 2g (CCDC:
1449503)
O
N
O
O
N
N
-N2
Ph
Ph
N
Ph
Ph
N
N
2
10
9
8
(2n, 2o). Similarly, propargylic ketones having a vinylic substituent
(1p) and an acetylenic substituent (1q) gave the corresponding
isoxazoles 2p and 2q in 67% and 66% yield, respectively. In addition,
4‐phenylpent‐1‐yn‐3‐one (1r) was not an appropriate starting
material under these reaction conditions. When the optically active
acetylenic ketone (R)‐1‐(2,2'‐diisopropoxy‐[1,1'‐binaphthalen]‐3‐
yl)prop‐2‐yn‐1‐one was examined as a substrate, to our delight, (R)‐
Scheme 2 A plausible reaction mechanism
On the basis of the preliminary results, a plausible pathway
is proposed for this cascade reaction (Scheme 2). Initially,
TMSN3 generates azido free radical associated with the
formation of intermediate
with CH3OH to form TEMPOH
radical subsequently attacks the alkyne to form radical
intermediate .Subsequently, the radical reacts directly with
the TEMPOH species , yields the intermediate which is
A
. The TEMPO‐TMS species
A reacts
5‐(2,2'‐diisopropoxy‐[1,1'‐binaphthalen]‐3‐yl)isoxazole
2s
was
B
and CH3O‐TMS. The azido free
formed in 55% yield.
To our disappointment, internal propargylic ketones could not
provide the desired product using the current catalytic system.
Internal propargylic ketone 3 was tested under the standard
conditions, providing the 4,5‐disubstituted 1,2,3‐triazole 4 in 82%
yield (eq 1).
Some control experiments were carried out in order to explore
the possible reaction pathway. CH318OH and 18O2 isotopic labeling
experiments were investigated. As expected, the oxygen atom of 2a
originated from propargylic ketone 1a (eqs 2 and 3, the results were
determined by HRMS, see SI). Furthermore, CH3OD was
investigated to the reaction and produced the deuterated product
2a‐d in 78% yield (eq 4). And the deuterated substrate 1a‐d` was
subjected to the reaction and produced the product 5‐
phenylisoxazole 2a‐d` in 77% yield (eq 5).
5
5
B
6
detected by HRMS (see SI), with the regeneration of the
catalyst. The intramolecular azide‐alkene cycloaddition was
performed to afford triazole species
undergoes homolytic cleavage to give radical intermediate
which release N2 to give the imine . Then, one‐electron shift,
7. This triazole 7
8,
9
followed by a subsequently intramolecular radical coupling to
afford the product 2a. The intermolecular [3+2] cycloaddition
reaction of Internal propargylic ketone with TMSN3 were
occurred during the standard conditions because of the effect
of steric hindrance.
Conclusions
In summary, we have demonstrated a facile transformation of
propargylic ketones into 5‐substituted isoxazoles catalyzed by
TEMPO. The reaction has been delineated to proceed by a
radical mechanism. Readily available, cheap starting substrates,
an inexpensive catalyst, metal‐free mild reaction conditions, a
simple experimental procedure, and good yields, are some of
the attractive attributes of the present protocol. Further work
concerning synthetic applications and biological assessment of
these isoxazoles is underway and the results shall be reported
in due course.
Experimental
General remarks
Melting points were measured with a SGW X‐4 melting point
instrument (uncorrected). Proton nuclear magnetic resonance
spectra (1H NMR) and carbon nuclear magnetic resonance spectra
(13C NMR) were recorded at 400 MHz and 100 MHz, respectively,
using CDCl3 as reference standard (δ 7.26 ppm) for 1H NMR and (δ
77 ppm) for 13C NMR. HRMS (ion trap) were recorded using ESI.
Precoated silica gel plates GF‐254 were used for thin‐layer analytical
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 4 of 7
ARTICLE
Journal Name
chromatography. Column chromatography was performed on silica 5‐(3‐(trifluoromethyl)phenyl)isoxazole (2h): white oil;1H NMR (400
View Article Online
gel (300‐400 mesh). Starting materials azidomethyl aromatics were MHz, CDCl3) δ 8.33 (d, J = 1.7 Hz, 1H), 8.03 (sD, 1OHI:)1,07.1.90389(/dC,6JR=A171.089H9Az,
readily prepared according to literature procedures. Unless 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 1.7
otherwise noted, all reagents were obtained commercially and used Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.72, 150.91, 132.10,
without further purification.
131.77, 131.44, 131.12, 129.65, 128.92, 128.91, 127.94, 126.72,
126.68, 126.65, 126.61, 124.97, 122.73, 122.69, 122.65, 122.61,
122.27, 99.68; ppm; HRMS (m/z) (APCI): calcd for C10H6F3NO
214.04797 [M+H+]; found 214.04721.
General procedure for the synthesis of 5‐Substituted Isoxazoles
To the mixture of propargylic ketones (1.0 equiv, 0.3 mmol) and
azides (1.5 equiv., 0.45 mmol), TEMPO (15 mol%), and 2.0 mL
CH3OH at 25 oC for 12 h in the air. PPh3 (1.0 equiv.) was added after
12 h and the mixture was stirred for another 1 h. The progress of
the reaction was monitored by thin‐layer chromatography. Upon
completion, the mixture was evaporated under reduced pressure,
and the residue was separated by column chromatography (ethyl
acetate/petroleum ether = 1:40 to 1:20) to give the pure product.
5‐phenylisoxazole (2a): colorless solid; m.p. 79‐81oC (lit.14 80‐81
oC);1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.78 (d, J = 7.1 Hz, 2H),
7.48–7.39 (m, 3H), 6.50 (s, 1H) ppm;13C NMR (100 MHz, CDCl3) δ
169.24, 150.73, 130.07, 128.88, 127.15, 125.73, 98.57 ppm; HRMS
(m/z) (ESI): calcd for C9H7NO 146.06059 [M+H+]; found 146.05994.
5‐(o‐tolyl)isoxazole (2b): white oil;1H NMR (400 MHz, CDCl3) δ 8.32
(d, J = 1.8 Hz, 1H), 7.72 (dd, J = 5.6, 3.5 Hz, 1H), 7.38–7.33 (m, 1H),
7.33–7.28 (m, 2H), 6.43 (d, J = 1.8 Hz, 1H), 2.51 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 169.39, 150.44, 136.16, 131.30, 129.97,
128.51, 126.84, 126.19, 101.73, 21.39 ppm; HRMS (m/z) (APCI):
calcd for C10H9NO 160.07624 [M+H+]; found 160.07557.
5‐(2‐bromo‐5‐methoxyphenyl)isoxazole (2i): colorless solid; m.p.
62‐65 oC; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 1.9 Hz, 1H), 7.55 (d,
J = 8.9 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.84
(dd, J = 8.9, 3.1 Hz, 1H), 3.83 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
δ 166.80, 158.88, 150.49, 134.85, 128.58, 117.71, 114.66, 111.38,
103.41, 55.58 ppm; HRMS (m/z) (APCI): calcd for C10H8BrNO2
253.98167 [M+H+]; found 253.98083.
5‐(4‐(tert‐butyl)phenyl)isoxazole (2j): white oil;1H NMR (400 MHz,
CDCl3) δ 8.26 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H),
6.47 (s, 1H), 1.35 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.43,
153.53, 150.70, 125.86, 125.60, 124.49, 98.07, 34.80, 31.07 ppm;
HRMS (m/z) (APCI): calcd for C13H15NO 202.12319 [M+H+]; found
202.12237.
5‐(naphthalen‐2‐yl)isoxazole (2k): colorless solid; m.p. 92‐94 oC
(lit.17 93‐95 oC); 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 10.5 Hz, 2H),
7.92–7.88 (m, 2H), 7.86–7.80 (m, 2H), 7.56–7.52 (m, 2H), 6.61 (s, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 169.35, 150.96, 133.80, 132.96,
128.77, 128.56, 127.74, 127.23, 126.83, 125.51, 124.39, 122.83,
98.99 ppm; HRMS (m/z) (APCI): calcd for C13H9NO 196.07624
[M+H+]; found 196.07550.
5‐(m‐tolyl)isoxazole (2c): light yellow oil; 1H NMR (400 MHz, CDCl3)
δ 8.27 (s, 1H), 7.59 (d, J = 11.3 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.24
(d, J = 7.6 Hz, 1H), 6.49 (s, 1H), 2.40 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 169.45, 150.69, 138.66, 130.88, 128.79, 127.08, 126.34,
122.92, 98.46, 21.26 ppm; HRMS (m/z) (APCI): calcd for C10H9NO
160.07624 [M+H+]; found 160.07556.
5‐(furan‐2‐yl)isoxazole (2l): light yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.26 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 6.92 (d, J =
3.4 Hz, 1H), 6.54 (dd, J = 3.3, 1.7 Hz, 1H), 6.45 (d, J = 1.6 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 161.05, 150.39, 144.05, 143.21, 111.91,
110.45, 98.25 ppm; HRMS (m/z) (APCI): calcd for C7H5NO2
136.03985 [M+H+]; found 136.03930.
o
5‐(p‐tolyl)isoxazole (2d): colorless solid; m.p. 55‐57 C (lit.15 60‐61
oC);1H NMR (500 MHz, CDCl3) δ 8.29 (d, J = 1.8 Hz, 1H), 7.71 (d, J =
8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.49 (d, J = 1.8 Hz, 1H), 2.42 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) δ 169.53, 150.74, 140.44,
129.64, 125.78, 124.58, 98.00, 21.41 ppm; HRMS (m/z) (APCI): calcd
for C10H9NO 160.07624 [M+H+]; found 160.07550.
5‐(thiophen‐2‐yl)isoxazole (2m): yellow oil; 1H NMR (500 MHz,
CDCl3) δ 8.25 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 3.7, 1.1 Hz, 1H), 7.44
(dd, J = 5.0, 1.1 Hz, 1H), 7.12 (dd, J = 5.0, 3.7 Hz, 1H), 6.38 (d, J = 1.8
Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ 164.25, 150.59, 128.98,
127.93, 127.87, 126.91, 98.28 ppm; HRMS (m/z) (ESI): calcd for
C7H5NOS 152.01701 [M+H+]; found 152.01649.
5‐(4‐fluorophenyl)isoxazole (2e): colorless solid; m.p. 46‐52 oC
(lit.16 51‐53 oC);1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 1.8 Hz, 1H),
7.81–7.74 (m, 2H), 7.19–7.12 (m, 2H), 6.47 (d, J = 1.8 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 168.43, 165.00, 162.51, 150.89, 127.99,
127.91, 123.69, 123.66, 116.34, 116.12, 98.46 ppm; HRMS (m/z)
(APCI): calcd for C9H6FNO 164.05117 [M+H+]; found 164.05047.
5‐(4‐chlorophenyl)isoxazole (2f): colorless solid; m.p. 79‐83 oC (lit.16
84‐85 oC);1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.72 (d, J = 8.4 Hz,
2H), 7.43 (d, J = 8.4 Hz, 2H), 6.50 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 168.20, 150.84, 136.20, 129.27, 127.07, 125.68, 98.94 ppm;
HRMS (m/z) (APCI): calcd for C9H6ClNO 180.02162 [M+H+]; found
180.02066.
5‐benzylisoxazole (2n): yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.11
(s, 1H), 7.31 (t, J = 7.1 Hz, 2H), 7.23 (d, J = 7.3 Hz, 3H), 5.89 (s, 1H),
4.08 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.46, 150.34,
135.88, 128.77, 127.12, 101.03, 33.01 ppm; HRMS (m/z) (APCI):
calcd for C10H9NO 160.07624 [M+H+]; found 160.07562.
1
5‐phenethylisoxazole (2o): yellow oil; H NMR (400 MHz, CDCl3) δ
8.13 (s, 1H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.18 (d, J
= 7.1 Hz, 2H), 5.93 (s, 1H), 3.11 (dd, J = 11.6, 4.7 Hz, 2H), 3.02 (dd, J
= 11.5, 4.8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.71, 150.20,
139.95, 128.51, 128.24, 126.41, 100.37, 33.56, 28.29 ppm; HRMS
(m/z) (APCI): calcd for C11H11NO 174.09189 [M+H+]; found
174.09128.
o
5‐(4‐bromophenyl)isoxazole (2g): colorless solid; m.p. 114‐115 C
(lit.16 114‐116 oC);1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 1.9 Hz, 1H),
7.66–7.63 (m, 2H), 7.60–7.57 (m, 2H), 6.51 (d, J = 1.9 Hz, 1H) ppm;
13C NMR (125 MHz, CDCl3) δ 168.26, 150.81, 132.24, 127.28, 126.14,
124.51, 99.00 ppm; HRMS (m/z) (APCI): calcd for C9H6BrNO
223.97110 [M+H+]; found 223.97028.
(E)‐5‐styrylisoxazole (2p): colorless solid; m.p. 41‐43 oC (lit.18 42‐43
1
oC); H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 1.7 Hz, 1H), 7.48–7.43
(m, 2H), 7.36–7.24 (m, 4H), 6.93 (d, J = 16.4 Hz, 1H), 6.20 (d, J = 1.7
Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.86, 150.62, 135.49,
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 5 of 7
Journal Name
ARTICLE
134.95, 129.17, 128.87, 127.10, 112.85, 100.67 ppm; HRMS (m/z)
(APCI): calcd for C11H9NO 172.07624 [M+H+]; found 172.07556.
5‐(phenylethynyl)isoxazole (2q): yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.32 (d, J = 1.7 Hz, 1H), 7.58 (dd, J = 7.9, 1.6 Hz, 2H), 7.44–
7.37 (m, 3H), 6.50 (d, J = 1.7 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3)
δ 153.08, 150.34, 131.86, 129.89, 128.56, 120.82, 107.02, 98.65,
75.29 ppm; HRMS (m/z) (APCI): calcd for C11H7NO 170.06059
[M+H+]; found 170.05984.
5064; (b) Y. Lee, Y. Koyama, M. Yonekawa aVniedw TA.rticTlaenOanklinae,
Macromolecules, 2009, 42, 7709.
DOI: 10.1039/C6RA11099A
4
(a) D. A. Hay, O. Fedorov, S. Martin, D. C. Singleton, C. Tallant, C.
Wells, S. Picaud, M. Philpott, O. P. Monteiro, C. M. Rogers, S. J.
Conway, T. P. C. Tumber, A. Rooney, C. Yapp, P. Filippakopoulos,
M. E. Bunnage, S. Mîller, S. Knapp, C. J. Schofield, P. E. Brennan,
J. Am. Chem. Soc. 2014, 136, 9308; (b) R. M. Kumbhare, U. B.
Kosurkar, M. Janaki Ramaiah, T. L. Dadmal, S. N. Pushpavalli
and M. Pal‐Bhadra, Bioorg. Med. Chem. Lett., 2012, 22, 5424;
(c) P. Ratcliffe, J. Maclean, L. Abernnethy, T. Clatkson, M.
Dempster, A. M. Easson, D. Edwards, K. Everett, H. Feilden, P.
Littlewood, D. McArthur, D. McGregor, H. MeLuskey, O. Nimz, L.
A. Nisbet, R. Palin, H. Tracey, G. Walker, Bioorg. Med. Chem.
Lett. 2011, 21, 2559; (d) J. Liu, L.‐F. Yu, J. B. Eaton, B. Caldarone,
K. Cavino, C. Ruiz, M. Terry, A. Fedolak, D. Wang, A. Ghavami,
D. A. Lowe, D. Brunner, R. J. Lukas and A. P. Kozikowski, J. Med.
Chem., 2011, 54, 7280.
(a) P. J. Lindsay‐Scott, A. Clarke, J. Richardson, Org. Lett. 2015, 17,
476; (b) R. C. F. Jones, A. Chatterley, R. Marty, W. M. Owtonb,
M. R. J. Elsegood, Chem. Commun. 2015, 51, 1112; (c) P. A.
Allegretti, E. M. Ferreira, Chem. Sci. 2013, 4, 1053; (d) B.
Heasley, Angew. Chem. Int. Ed. 2011, 50, 8474; (e) V. Singh, R.
Saxena, S. Batra, J. Org. Chem. 2005, 70, 353.
(a) J. P. Waldo and R. C. Larock, Org. Lett., 2005, 7, 5203; (b) J. P.
Waldo and R. C. Larock, J. Org. Chem., 2007, 72, 9643; (c) Z.
She, D. Niu, L. Chen, M. A. Gunawan, X. Shanja, W. H. Hersh
and Y. Chen, J. Org. Chem., 2012, 77, 3627; (d) M. Ueda, S.
Sugita, A. Sato, T. Miyoshi and O. Miyata, J. Org. Chem., 2012,
77, 9344; (e) A. Sperança, B. Godoi, and G. Zeni, J. Org. Chem.,
2013, 78, 1630; (f) Y. Jeong, B. I. Kim, J. K. Lee and J. S. Ryu, J.
Org. Chem., 2014, 79, 6444; (g) W. Chen, B. Wang, N. Liu, D.
Huang, X. Wang and Y. Hu, Org. Lett., 2014, 16, 6140.
(a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman, K.
B. Sharpless, and V. V. Fokin, J. Am. Chem. Soc., 2005, 127, 210;
(b) S. Grecian and V. V. Fokin, Angew. Chem. Int. Ed., 2008, 47,
8285; (c) H. Zheng, R. McDonald and D. G Hall, Chem. Eur. J.,
2010, 16, 5454; (d) A. M. Jawalekar, E. Reubsaet, F. P. J. T.
Rutjes and F. L. V. Delft, Chem. Commun., 2011, 47, 3198; (e) D.
C. Schmitt, L. Lam and J. S. Johnson, Org. Lett., 2011, 13, 5136;
(f) W. Chen, J. Zhang, B. Wang, Z., Zhao, X. Wang and Y. Hu, J.
Org. Chem., 2015, 80, 2413; (g) K. C. Coffman, T. A. Palazzo, T. P.
Hartley, J. C. Fettinger, D. J. Tantillo and M. J. Kurth, Org. Lett.,
2013, 15, 2062; (h) M. Hu, X. He, Z. Niu, Z. Yan, F. Zhou and Y.
Shang, Synthesis, 2014, 46, 510.
(a) S. Tang, J. He, Y. Sun, L. He and X. She, J. Org. Chem., 2010, 75,
1961; (b) D. Xiang, X. Xin, X. Liu, R. Zhang, J. Yang and D. Dong,
Org. Lett., 2012, 41, 644; (c) P. Gao, H. X. Li, X. H. Hao, D. P. Jin,
D. Q. Chen, X. B. Yan, X. X. Wu, X. R. Song, X. Y. Liu and Y. M.
Liang, Org. Lett., 2014, 16, 6298; (d) R. Harigae, K. Moriyama
and H. Togo, J. Org. Chem., 2014, 79, 2049.
5‐(1‐phenylethyl)isoxazole(2r): yellow oil; HRMS (m/z) (ESI): calcd
for C11H11NO 173.08406 [M‐H+]; found 172.07597.
(R)‐5‐(2,2'‐diisopropoxy‐[1,1'‐binaphthalen]‐3‐yl)isoxazole
(2s):
20
1
light yellow oil; [α] = +62 (c 0.22, CH3OH); H NMR (400 MHz,
D
CDCl3) δ 8.56 (s, 1H), 8.34 (t, J = 3.8 Hz, 1H), 7.96 (dd, J = 8.4, 5.0 Hz,
2H), 7.85 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.34–7.30 (m,
1H), 7.24 (dd, J = 12.9, 6.3 Hz, 3H), 7.18 (d, J = 8.4 Hz, 1H), 6.97 (d, J
= 1.2 Hz, 1H), 4.55 (dt, J = 11.9, 5.9 Hz, 1H), 3.87–3.78 (m, 1H), 1.15
(d, J = 5.9 Hz, 3H), 1.02 (d, J = 6.0 Hz, 3H), 0.81 (d, J = 6.1 Hz, 3H),
0.69 (d, J = 6.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.17,
152.78, 150.33, 150.09, 133.91, 133.07, 129.16, 129.02, 128.07,
127.92, 127.36, 127.11, 126.27, 125.85, 125.61, 124.95, 124.44,
124.30, 122.77, 121.40, 119.13, 114.60, 102.89, 75.13, 69.92, 21.55,
21.50, 21.39 ppm; HRMS (m/z) (ESI): calcd for C29H28NO3 438.20692
[M+H+]; found 438.20599.
5
6
Acknowledgements
We would like to thank National Natural Science Foundation of
China (21362002 and 81260472), State Key Laboratory for
Chemistry and Molecular Engineering of Medicinal Resources
(CMEMR2014‐A02 and CMEMR2012‐A20), Guangxi’s Medicine
Talented Persons Small Highland Foundation (1306), and The
Fund of Guangxi Key Laboratory of Functional Phytochemicals
Research and Utilization (FPRU2015‐2) for financial support.
7
Notes and references
1
(a) A. M. S. Silva, A. C. Tome and T. M. V. Pinho e Melo, J. Elguero,
in: Modern Heterocyclic Chemistry, (Eds.: J. Alvarez‐Builla, J. J.
Vaquero, J. Barluenga), Wiley‐VCH, Weinheim, 2011, 727–808;
(b) B. J. Wakefield, in: Science of Synthesis: HoubenWeyl
Methods of Molecular Transformations, Vol. 11, (Ed.: E.
Schaumann), Georg Thieme Verlag, Stuttgart, New York, 2004,
229–288; (c) T. M. V. D. Pinho e Melo, Curr. Org. Chem., 2005,
9, 925.
8
9
2
(a) M. Eda, T. Kuroda, S. Kaneko, Y. Aoki, M. Yamashita, C.
Okumura, Y. Ikeda, T. Ohbora, M. Sakaue, N. Koyama and K.
Aritomo, J. Med. Chem., 2015, 58, 4918; (b) N. Ye, Y.‐m. Zhu,
H.‐j. Chen, Z.‐q. Liu, F.‐C. Mei, C. Wild, H.‐y. Chen, X.‐d. Cheng
and J. Zhou, J. Med. Chem., 2015, 58, 6033; (c) M. Koufaki, A.
Tsatsaroni, X. Alexi, H. Guerrand, S. Zerva and M. N. Alexis,
Bioorg. Med. Chem., 2011, 19, 4841; (d) D. A. Patrick, S. A.
Bakunov, S. M. Bakunova, E. V. K. S. Kumar, R. J. Lombardy, S. K.
Jones, A. S. Bridges, O. Zhirnov, J. E. Hall, T. Wenzler, R. Brun
and R. R. Tidwell, J. Med. Chem., 2007, 50, 2468–2485.
(a) A. D. Burrows, C. G. Frost, M. F. Mahon, P. R. Raithby, C.
Richardson and A. J. Stevenson, Chem. Commun., 2010, 46,
G. R. Kumar, Y. K. Kumar and M. S. Reddy, Chem. Commun., 2016,
52, 6589.
10 (a) P. Passacantilli, S. Pepe, Gi. Piancatelli, D. Pigini and A.
Squarcia, Tetrahedron, 2004, 60, 6453; (b) H. G. Weinig, P.
Passacantilli, M. Colapietro and G. Piancatelli, Tetrahedron
Lett., 2002, 43, 4613; (c) F. A. Rosa, P. Machado, H. G.
Bonacorso, N. Zanatta and M. A. P. Martins, J. Heterocyclic
3
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 5
Please do not adjust margins

Please do not adjust margins
RSC Advances
Page 6 of 7
ARTICLE
Journal Name
Chem., 2008, 45, 879; (d) R.M. Adlington, J. E. Baldwin, D.
View Article Online
DOI: 10.1039/C6RA11099A
Catterick, G. J. Pritchard and L. T. Tang, J. Chem. Soc., Perkin
Trans. 1, 2000, 2311; (e) D.H. Churykau, O. G. Kulinkovich,
Synlett, 2006, 20, 3427; (f) U. Klein and W. Steglich, Liebigs
Ann. Chem., 1989, 247.
11 (a) L. S. Aitken, N. R. Arezki, A. Dell'Isola and A. J. A. Cobb,
Synthesis, 2013, 45, 2627; (b) A. S. Kucherenko, D. E. Siyutkin,
O. V. Maltsev, S. V. Kochetkov and S. G. Zlotin, Russ. Chem.
Bull., 2012, 61, 1313; (c) B. Bradshaw and J. Bonjoch, Synlett,
2012, 23, 337; (d) A. Łukasz, J. Hao, and A. J. Karl, Angew.
Chem. Int. Ed., 2011, 50, 8492; (e) M. Benaglia and S. Rossi,
Org. Biomol. Chem., 2010, 8, 3824.
12 (a) P. Galletti, M. Pori, F. Funiciello, R. Soldati, A. Ballardini and D.
Giacomini, ChemSusChem, 2014, 7, 2684; (b) N. Tamura, T.
Aoyama, T. Takido and M. Kodomari, Synlett, 2012, 23, 1397; (c)
T. Ludger and S. Armido, Angew. Chem. Int. Ed., 2011, 50, 5034;
(d) X. Q. Li and C. Zhang, Synthesis, 2009, 1163.
13 T. Wang and N. Jiao, J. Am. Chem. Soc., 2013, 135, 11692.
14 K. Bowden and E. R. H. Jones, J. Chem. Soc., 1946, 953.
15 Y. I. Lin and S. A. Lang Jr, J. Org. Chem. 1980, 45, 4857.
16 F. A. Rosa, P. Machado, H. G. Bonacorso, N. Zanatta, M. A. P.
Martins, Journal of Heterocyclic Chemistry, 2008, 45, 879.
17 E. V. Vashkevich, V. I. Potkin, N. G. Kozlov, Russian Journal of
Organic Chemistry (Translation of Zhurnal Organicheskoi
Khimii), 2004, 40, 1503.
18 L. Panizzi, Monti, Elios, Gazzetta Chimica Italiana, 1947, 77, 556.
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 7 of 7
RSC Advances
View Article Online
DOI: 10.1039/C6RA11099A
Graphic abstract
TEMPO-catalyzed Synthesis of 5-Substituted Isoxazoles from
Propargylic Ketones and TMSN3
+a
+a
Yan He, Yu-yang Xie, Ying-chun Wang,ab Xiao-min Bin,a Da-chao Hu,a Heng-shan Wang*a and
Ying-ming Pan*a
A novel and efficient TEMPO-catalyzed synthesis of 5-substituted isoxazoles from propargylic
ketones and TMSN3 via the radical mechanism process is described. This methodology provides
an easy access to a variety of useful 5-substituted isoxazoles from simple and readily available
propargylic ketones and TMSN3 in good to excellent yields. A plausible reaction mechanism for
this process is proposed.