Tetrahedron Letters 59 (2018) 1159–1171

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Digest paper

Recent progresses in the synthesis of functionalized isoxazoles

Taiki Morita, Somaraju Yugandar, Shinichiro Fuse, Hiroyuki Nakamura ⇑
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho Midori-ku, Yokohama 226-8503, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Isoxazole is an important pharmacophore that is critical for biological activity. The isoxazole ring ranks
Received 27 December 2017 33rd in frequency among the 351 ring systems found in marketed drugs, thus suggesting a great deal of
Revised 7 February 2018 interest in the synthesis of functional isoxazoles. In recent years, various approaches have been devel-
Accepted 8 February 2018
oped for the synthesis and functionalization of isoxazoles. This comprehensive survey summarizes the
Available online 10 February 2018
recent new synthetic approaches to functionalized isoxazoles, with particular focus on the last three
years with regard to the following reaction types: (1) 1,3-dipolar cycloaddition, (2) condensation, (3)
Keywords:
cycloisomerization, and (4) direct functionalization.
Isoxazole
Cycloaddition
Ó 2018 Elsevier Ltd. All rights reserved.
Condensation
Cycloisomerization
Functionalization

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1159
1,3-Dipolar cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
Condensation reactions using 1,3-dicarbonyl derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1163
Cycloisomerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1166
Intramolecular nitro group addition to unsaturated CAC bonds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
Direct functionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170

Introduction currently marketed drugs, thus suggesting a great deal of interest

in the synthesis of functional isoxazoles.1
Isoxazole is a five-membered heteroaromatic ring that contains In recent years, various approaches have been developed for the
contiguous nitrogen and oxygen atoms. It is an important frame- synthesis and functionalization of isoxazoles. They have been sum-
work and a critical pharmacophore for biological activity. The isox- marized in several authoritative reviews. Especially notable is the
azole ring has desirable pharmacological activity because its two comprehensive review published by Hu and Szostak1b in 2015 on
contiguous electronegative heteroatoms contribute to hydrogen the synthesis, reaction mechanisms, and reactivity of isoxazoles,
donor–acceptor interactions, with various target enzymes and including synthetically useful metal-catalyzed reactions.
receptors inaccessible by other ring systems. Indeed, the isoxazole In this summary, a comprehensive survey of recent progress in
ring ranks 33rd in frequency among the 351 ring systems found in the synthesis of functionalized isoxazoles, particularly over the last
three years, is presented. The review discusses new synthetic
approaches to functionalized isoxazoles based on the following
four reaction types: (1) 1,3-dipolar cycloaddition, (2) condensation,
⇑ Corresponding author.
(3) cycloisomerization, and (4) direct functionalization (Fig. 1).
E-mail address: hiro@res.titech.ac.jp (H. Nakamura).

https://doi.org/10.1016/j.tetlet.2018.02.020
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
1160 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171

R N O
F
R
NOH NCS F
O 5
F F N
CHCl3, rt N O
F F F
4a 2b R F
NR'2 R
6
N O N O N O
F F OH F
CO2Et O
F F F BocN
Fig. 1. Synthetic approaches of functionalized isoxazoles.1b 5a, 73% 5b, 67% 5c, 48%

N O N O N O
F F F
1,3-Dipolar cycloaddition
F CO2Et F CN F
O
One of the best established routes to isoxazole synthesis is the 6a, 80% 6b, 34% 6c,47%
1,3-dipolar cycloaddition of nitrile oxides to alkynes/alkenes. The
reaction of nitrile oxides with alkynes proceeds under thermal con- Scheme 2. Synthesis of 3-difluoromethyl isoxazoles 5 and 6.
ditions; however, the regioselectivity is very poor because of the
high activation energy to the reaction.2 Fokin et al.3 reported a cop-
per-catalyzed 1,3-dipolar cycloaddition of alkynes with nitrile oxi-
des generated from oxime halides under basic conditions in 2005.
This strategy enabled the synthesis of functionalized isoxazoles in
high yields and regioselectivities under mild conditions. Nowa-
days, both metal-catalyzed and metal-free 1,3-dipolar cycloaddi-
tions have been developed under mild conditions to access
functionalized isoxazoles.
The synthesis of (per)fluoroalkyl isoxazoles has been developed
vigorously because of the biological importance of fluorinated
compounds. For example, Ley et al.4 reported the synthesis of 3-tri-
fluoromethylisoxazoles. They prepared hydroximoyl bromide 1a as
a precursor to nitrile oxide 2a from a commercially available triflu-
oromethylated hemiacetal in two steps. Bromide 1a was readily
converted into the corresponding nitrile oxide under basic condi-
tions for reacting with terminal alkynes to yield the corresponding
3-trifluoromethyl-5-substituted isoxazoles 3 in good to high yields
Scheme 3. One-pot synthesis of 3-trifluoromethyl-4-iodoisoxazole 7.
(Scheme 1). The combination of base/solvent affected the 1,3-dipo-
lar cycloaddition yields greatly: trimethylamine/toluene was suit-
able for aromatic alkynes, whereas Na2CO3/H2O was suitable for
aliphatic alkynes. Furthermore, difluoromethyl-substituted isoxa- the isoxazoles 9. By contrast, 3-chloro-4-iodoisoxazoles were
zoles were synthesized through the 1,3-dipolar cycloaddition of synthesized from dichloroaldoxime 1c (Scheme 4).7 The use of cop-
difluoromethyl nitrile oxides generated from oxime 4a to alkynes per acetylide was the key to preventing the dimerization of the
and enamines (Scheme 2).5 nitrile oxide. The combination of alkynylcopper(I) and molecular
The one-pot synthesis of 3-trifluoromethyl-4-iodoisoxazoles iodine was used as a synthetic equivalent to 1-iodoalkyne. The tri-
from trifluoromethylated oxime 1b and alkynes was demonstrated ple bond of 1-iodoalkyne was activated by coordination to CuI and
by Wu et al.6 The reaction of 1b with phenylacetylene proceeded at reacted with a-chloronitrile oxide to yield 3-chloro-4-iodoisoxa-
room temperature to afford 4-iodo-5-phenyl-3-(trifluoromethyl) zoles 11 as a novel building block with a broad substrate scope.
isoxazole (7), a useful building block for further functionalization Hamme II et al.8 prepared a series of 4-bromo spiroisoxazolines
at the C4 position (Scheme 3). The proposed isoxazole ring 14 containing various aliphatic and aromatic substituents at the
construction of the mechanistic studies did not occur through
1,3-dipolar cycloaddition; however, a stepwise bond formation
mechanism was invoked. The resulting intermediate reacted with
N-iodosuccinimide (NIS) to install iodine at the C-4 position of

Scheme 1. Synthesis of 3-trifluoromethylisoxazoles 3 using hydroximoyl bromide

1a. Scheme 4. One-pot synthesis of 3-chloro-4-iodo isoxazoles 11.
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171 1161

OH
R1 N
X OH R
Cl
N Br3 R1
R1 O N
n R R1 H O
X X
R1 R
NEt3, CH2Cl2 N OH K2CO3, CH2Cl2 Br R1
n
O n
12 13 Cl 14
n = 1, 2 O N 16 examples
X = H2, O O (61-80%)

Br Cl
14a

Scheme 5. Synthesis of furan, pyran, and lactone containing spiroisoxazolines 14.

Scheme 8. Synthesis of 4-difluoromethyl isoxazoles 20.

the most prominent anti-cancer activity toward breast cancer cell

Scheme 6. Generation of nitrile oxide in aqueous solutions.
lines MCF-7 and MDA-MB-231, with IC50 values of 52.4 and 43.1
lM, respectively.
It should be noted that nitrile oxides are usually prepared from
the corresponding oxime halides 1 in organic solvents under basic
conditions. However, Kittakoop et al.9 succeeded in the generation
of nitrile oxides under acidic aqueous conditions (pH 4–5) at room
temperature. The generated nitrile oxides reacted with alkynes
readily in water to give the corresponding di- and trisubstituted
isoxazoles 15 (Scheme 6). This reaction has become an alternative
bioconjugation tool for chemical biology. A related biological
application was reported by Gopi et al.10 They demonstrated an
orthogonally chemoselective nitrile oxide-alkyne 1,3-dipolar
cycloaddition by using both nitro and azide functionalized pep-
tides. Peptide 16 was first subjected to 1,3-dipolar cycloaddition
with N-Cbz-propargylamine in the presence of phenyl isocyanate.
The resulting isoxazole-containing peptide 17 was subjected to
an alkyne–azide click reaction with phenylacetylene in the pres-
ence of copper catalysts to afford double-conjugated peptide 18
(Scheme 7).
By way of 1,3-dipolar cycloaddition, various fluorinated alkynes
have been reported as building blocks for isoxazole formation.
Shibata et al.11 developed a one-step synthesis of difluoromethyl
alkynes 19 that could undergo 1,3-dipolar cycloaddition
with in-situ generated nitrile oxides to yield the corresponding

Scheme 7. Orthogonal cycloadditions using azide and nitro group.

3-position via 1,3-dipolar cycloaddition followed by the

intramolecular cyclization of a pendant hydroxyl or carboxylic acid
group (Scheme 5). Among these molecules, compound 14a showed Scheme 9. Electrochemical fluorination of propargylic thioethers 21.
1162 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 10. Organocatalyst-induced 1,3-dipolar cycloaddition of hydroximoyl
chloride 1 with b-functionalized ketones 24.
Scheme 11. NHC-catalyzed domino addition of allenyl Grignard reagent 26 to
nitrile oxide 2c.
4-difluoromethyl isoxazoles 20 (Scheme 8). Electrochemical fluori-
nation is also useful for the synthesis of partially fluorinated termi-
nal alkynes. Mono-/di-fluorinations were selectively controlled
depending on the HF salt used and electricity. Fuchigami et al.12
demonstrated the copper-catalyzed 1,3-dipolar cycloaddition of
mono-/di-fluorinated propargylic thioethers 22 with nitrile oxides
derived from an imidoyl chloride to afford isoxazoles 23
(Scheme 9).
Organocatalysts can also be used to induce the 1,3-dipolar
cycloaddition of nitrile oxides with b-functionalized ketones 24
to synthesize 3,4,5-trisubstituted isoxazoles (Scheme 10). In
this transformation, organocatalyst 1,1,3,3-tetramethylguanidine
Scheme 12. Generation of nitrile oxide 2 using isoamyl nitrite 33.
(TMG) was reacted with b-keto amides to generate enolates that
could undergo 1,3-dipolar cycloaddition with nitrile oxide to afford
the corresponding isoxazoles 25.13
In addition to enolates, allenyl Grignard reagent 26 underwent
1,3-dipolar cycloaddition with nitrile oxides. Vasam et al.14
reported the N-heterocyclic carbene (NHC)-catalyzed domino
addition of allenyl Grignard reagents to aryl nitrile oxide
(Scheme 11). This reaction rapidly furnished 5-(3-butynyl)isoxa-
zole 27 under mild conditions in good yields. During the reaction,
the NHC precursor would be first activated by the allenyl Grignard
reagent; thereafter, intermediate 30 would be formed by reacting
with a second allenyl Grignard molecule. Intermediate 30 reacts
with nitrile oxide to form isoxazoles 31. Thereafter, 31 reacts with
yet another allenyl Grignard reagent to induce coupling between
the allenyl carbon and the isoxazole-substituted methylene carbon
to afford the product 27 and regenerate the catalyst.
Although hydroximoyl halides are the most common precursors
for nitrile oxides, other nitrile oxides, or their equivalents, building
blocks have been developed for the structural diversity and step-
economical manipulations of isoxazoles. For example, isoamyl
nitrite (33) was used as an oxidant to generate nitrile oxide from
aldoxime. In this reaction, isoamyl alcohol and nitroxyl were gen-
erated, along with the formation of nitrile oxide. This in-situ
formed nitrile oxide could react with alkynes to afford 3,5-disub-
stituted isoxazoles in a one-pot procedure (Scheme 12).15 Hyperva-
lent iodine was also used as an alternative oxidant for the
generation of nitrile oxide from aldoxime.16 In this reaction, the
nucleophilic oxygen atom of the benzaldehyde oxime attacks the
electrophilic iodine center, thus leading to the release of one acet-
ate from PhI(OAc)2 and phenyl iodide and to the generation of the
cationic intermediate 38. The proton from the benzylic position of
the cationic intermediate 38 is abstracted by the acetate to form
nitrile oxide (Scheme 13).17
Nitroso-nitro enamine 39 was also used as a nitrile oxide pre-
cursor. The nitroso-nitro enamine was prepared from 2-(nitro-
methylene)pyrrolidine by using sodium nitrite and acetic acid.
The corresponding nitrile oxide 43 was generated from nitroso-
nitro enamine at 90 °C and reacted with alkynes to provide isoxa-
zoles 40 and 41 (Scheme 14).18 Compound 40, which contains an
oxime moiety, was obtained as the major product and with high
selectivity in some cases. According to the mechanistic study using
a 15N-labeled nitroso-nitro enamine, nitrile oxide 43 was gener-
ated by the elimination of a nitro group as HNO2. The isoxazoles
generated by the cycloaddition of nitrile oxide 43 with alkynes
result in two isomers due to tautomerization. The enamine form
45 would trap a nitronium ion to afford isoxazoles 40.
Another interesting approach toward the generation of nitrile
oxide species was demonstrated by Yang et al.19 Nitrile oxide
was prepared from 2-ethylazaarene 47, K2S2O8, and KNO3 (as a
nitrogen source) in the presence of catalytic CuBr (Scheme 15). In
this reaction, the cationic intermediate 50 is formed via hydrogen
atom abstraction by a sulfate radical anion and subsequent
oxidation by Cu(II). A possible pathway to ketone 52 would be
the trapping of 50 with NO–3 followed by the elimination of
Scheme 13. Generation of nitrile oxide from aldoxime 4a using PhI(OAc)2.
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 14. Generation of nitrile oxide from nitroso-nitro enamine 39 for the
synthesis of isoxazoles.
Scheme 15. Copper-catalyzed synthesis of isoxazoles 48 from 2-ethylazaarene 47.
Scheme 16. Synthesis of 5-acyl-3-cyanoisoxazoles 59.
1163
HNO2. The Cu(I)-enolate 53 generated from ketone 52 reacts with
the NO2 radical to provide the nitrile oxide 55 through benzylic
radical species 54.
Nishiwaki et al.20 developed novel dianionic reagent 57 from
the pyridium salt of nitroisoxazolone 56 to synthesize 3-cyano-5-
acylisoxazoles (Scheme 16). In this reaction, dianionic reagent 57
serves as a masked version of highly explosive nitro-acetonitrile.
The first step is considered the decarboxylation/Michael addition
of 57 to enone 58 to produce intermediate 60. Thereafter, cycliza-
tion forms isoxazoline 61. A subsequent proton transfer yields 63,
and dehydration furnishes the final product 59. In the other possi-
ble mechanistic pathway, 60 would undergo the elimination of
hydrochloric acid (HCl) to afford enone 62. The subsequent cycliza-
tion would lead to isoxazoline 63.
Condensation reactions using 1,3-dicarbonyl derivatives
Another frequently invested approach to isoxazoles is the con-
densation reaction of hydroxylamine with 1,3-dicarbonyl com-
pounds or its equivalents, such as a,b-unsaturated carbonyl
compounds. In this approach, the isoxazole ring is constructed
from a three-carbon unit and a small component possessing a
NAO bond. In general, relatively harsh reaction conditions are
required for this condensation approach; thus, the reaction scope
and synthetic diversity are limited. However, some useful methods
for the synthesis of isoxazoles via condensations have been
reported recently.
Langer et al.21 reported the synthesis of isoxale-5-carboxylates
by the cyclization of oxime dianions with diethyl oxalate in
2006. On the basis of this strategy, they demonstrated an efficient
one-pot synthesis of 5-perfluoroalkyl pyrazoles and 5-trifluo-
romethyl isoxazoles via a hydrazone dianion species (Scheme 17).22
Dianions 65 were prepared by treating oximes with 2.2 equivalents
of n-BuLi and reacted with trifluoroacetate to afford 5-trifluo-
romethyl isoxazoles 67.
The development of novel 1,3-dicarbonyl equivalents enables
easy accesses to highly functionalized isoxazoles. Leroux et al.23
succeeded in the preparation of fluorinated iminium salt 69 from
commercially available 1,1,2,2-tetrafluoro-N,N-dimethylethan-1-
amine (68). The iminium salt 69 was trapped with ethyl cyanoac-
etate or malononitrile to give the corresponding enaminones. The
reaction of these enaminones with hydroxyl amine resulted in
highly functionalized isoxazoles 71 quantitatively (Scheme 18).
Furthermore, fluoro(trifluoromethoxy)methyl-substituted isoxa-
zoles 76 were synthesized from commercially available trifluo-
romethyl trifluorovinyl ether (72) (Scheme 19).24 The key aspect
of this transformation is the preparation of fluoro(trifluo-
romethoxy) iminium salt 74 from trifluoromethyl trifluorovinyl
ether (72). Perfluorinated isoxazoles 76 were obtained in a similar
manner to the protocol described in Scheme 18.
b-Oxodithioesters have also been used as 1,3-dicarbonyl deriva-
tives to synthesize 3-methylthio-isoxazoles. Various 3-methylthio-
Scheme 17. One-pot synthesis of 5-trifluoromethyl isoxazoles 67.
1164 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 18. Synthesis of 3-difluoromethyl isoxazoles 71 from fluorinated iminium
salt 69.
Scheme 19. Synthesis of 3-fluoro(trifluoromethoxy)methyl isoxazoles 76 using
perfluorinated iminium salt 74.
Scheme 20. Synthesis of 3-methylthio isoxazoles 78 from b-oxo dithioesters 77.
5-aryl-isoxazoles 78 were synthesized from b-oxodithioesters with
hydroxylamine under acidic conditions (Scheme 20).25 The use of
HOAc as a solvent is essential for isoxazole ring formation: b-
ketonitriles were obtained when the reaction was performed in
ethanol. By contrast, 5-methylthio isoxazoles 80 were obtained
from the reaction of a-oxo ketene dithioacetals 79 with hydroxy-
lamine under basic conditions (Scheme 21).26
Zhang et al.27 reported a one-pot synthesis of trisubstituted
isoxazoles from tertiary propargyl alcohol 81 (Scheme 22).
Scheme 21. Synthesis of 5-methylthio isoxazoles 80 from a-oxo ketene dithioac-
etals 79.
Scheme 22. One-pot synthesis of isoxazoles 82 via tandem oxidation/1,2-migration
of propargyl alcohol 81.
a-Heteroaryl-substituted 1,3-diketones generated from the gold-
catalyzed oxidation/1,2-heteroaryl group migration cascade
through key gold carbene intermediates 84. The corresponding
trisubstituted isoxazoles 82 were obtained after reacting with
hydroxylamine under basic conditions.
Ynones are conventionally used as 1,3-dicarbonyl derivatives
with hydroxylamine or its equivalents to synthesize isoxazoles.
By contrast, Reddy et al.28 disclosed the reaction of ynones with
trimethylsilylazide as a nitrogen source to afford 3,5-disubstituted
isoxazoles (Scheme 23). According to their proposed mechanism,
the coordination of the TMS group in TMSN3 with the ynone oxy-
gen enables a syn-Michael addition to the carbonyl group, thus
generating vinyl azide 89. Two pathways were proposed for isoxa-
zole formation: direct cyclization releasing nitrogen gas or forma-
tion of azirine followed by isomerization. A similar transformation
was demonstrated using ynones with the azide ion to synthesize 5-
aminoisoxazoles 92 (Scheme 24).29 The removal of the alkyne
trimethylsilyl group first proceeds under basic conditions, and
the syn-Michael adducts form the corresponding isoxazoles.
Since Yu and Bao30 first reported the synthesis of 3,5-disubsti-
tuted isoxazoles in 2012, variously functionalized diynes have
been employed for the mild intramolecular Cope-type hydroami-
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 23. Synthesis of 3,5-disubstituted isoxazoles 34 from ynones 87 and
TMSN3.
Scheme 24. Synthesis of 5-aminoisoxazoles 92 from ynones 91 and sodium azide.
Scheme 25. Synthesis of isoxazole-tethered phosphine oxides 96a and 96b from
1-phosphonyl 2,4-diyne 95.
Scheme 26. Synthesis of 3-trifluoroethylisoxazole 100 using conjugated diyne 98.
nation of 1,3-dialkynes with hydroxylamine and subsequent elec-
trophilic addition method. For example, Shen and Han31 developed
a copper-catalyzed synthesis of 1-phosphonyl 2,4-diynes 95 and
converted them to isoxazole-tethered phosphine oxides 96a and
1165
Scheme 27. Synthesis of 5-bromoisoxazoles 102 from 1,1-dibromocyclopropanes
101.
Scheme 28. DBU-mediated synthesis of fully substituted isoxazoles 106 from
electron-deficient cyclopropanes 105 and nitromethane.
96b (mixture of regioisomers, Scheme 25). The trifluoroethylated
diynes prepared by the copper-mediated trifluoroethylation of
conjugated diynes were also converted to the corresponding 3-tri-
fluoroethyl isoxazole 100 (Scheme 26),32 although the regioselec-
tivity was not reported.
Cyclopropanes can serve as a three-carbon unit for the synthe-
sis of isoxazoles. Bondarenko et al.33 reported the nitrosation of 2-
aryl-1,1-dibromocyclopropanes 101 to afford 5-bromoisoxazoles
(Scheme 27). The ring opening of cyclopropane is triggered by
the nitrosonium ion to yield dibromocarbocation 103, which
Scheme 29. Synthesis of 4-methylenated isoxazoline derivatives 113.
1166 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
undergoes intramolecular cyclization followed by the elimination
of HBr to afford 5-bromoisoxazoles. Alternatively, nitromethane
was used for the construction of isoxazoles through [3+2] cycload-
dition with highly electron-deficient cyclopropanes (Scheme 28).34
The DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)-promoted ring
opening of the cyclopropanes afforded the thermodynamically
stable carbanion species 107. The tautomer of 107 undergoes a for-
mal 1,3-dipolar cycloaddition with nitromethane to yield the cor-
responding isoxazole-5-carboxylates through 5-membered
heterocyclic intermediates.
Cycloisomerization
Cycloisomerization is a powerful method in terms of the gener-
ation of intrinsic atom-economy structural complexity in organic
synthesis.35 In this section, we cover the recent advances in isoxa-
zole synthesis via cycloisomerization under both metal-catalyzed
and metal-free conditions.
Nakamura et al.36 developed a skeletal rearrangement of O-
propargylic formaldoximes 112 in the presence of a gold catalyst
for the preparation of 4-methylenated isoxazoline derivatives
113 via a unique intermolecular methylene transfer pathway.
Thereafter, these isoxazolines underwent isomerization or an ene
reaction with maleimide, azodicarboxylate, and glyoxalate to pro-
vide the corresponding functionalized isoxazoles114–117
(Scheme 29). Furthermore, this system can be used for the synthe-
sis of chiral isoxazole 120 from enantioenriched O-propargylic
oxime 118 through chirality transfer (Scheme 30).37 Interestingly,
the chirality of the enantioenriched O-propargylic oxime 118 was
completely retained during the gold-catalyzed skeletal rearrange-
ment/ene reaction cascade.
Thongsornkleeb et al.38 reported the synthesis of 4-chloroisox-
azole 122 from (E/Z)-alkynyl-O-methyl oximes 121 via chlorinative
cyclization (Scheme 31). The combination of N-chlorosuccinimide
(NCS) and chlorotrimethylsilane (TMSCl) is essential for generating
chlorine (Cl2) and HCl in situ. Non-cyclizable (E)-Alkynyl-O-methyl
oximes were readily isomerized to the (Z)-isomers under mild
conditions for the desired isoxazole cyclization. 4-Bromo- and
4-iodoisoxazoles were prepared analogously by using N-bromo-
succinimide and NIS.
Scheme 30. Synthesis of enantioenriched isoxazole 120.
Scheme 31. Intramolecular cyclization of (E/Z)-alkyl-O-methyl oximes to isoxa-
zoles 122.
Strong electrophiles, such as oxocarbenium cations, also pro-
mote the intramolecular cyclization of alkynyl-O-methyl oximes.
4-[Alkoxy(aryl)methyl]-substituted isoxazoles 124 were synthe-
sized from alkynyl-O-methyl oximes 123 and aromatic acetals
(Scheme 32).39 The generation of oxocarbenium cations from the
acetals in the presence of boron trifluoride was essential for acti-
vating the alkynyl-O-methyl oxime triple bond. The intramolecular
5-endo dig cyclization was induced to afford the corresponding
isoxazoles. However, the reaction was limited to electron-donating
alkoxy groups at R1 of the alkynyl-O-methyl oximes.
Miyata and Ueda et al.40 reported the gold-catalyzed sequential
cyclization/[3,3]-sigmatropic rearrangements of O-allyl hydroxam-
ates 125 for the synthesis of 4-allyl-3-hydroxyisoxazoles 126
(Scheme 33). They previously reported the direct synthesis of
trisubstituted isoxazole 129 through a gold-catalyzed domino
reaction of alkynyl oxime ether 128.41 The similar transformation
proceeded with O-allyl hydroxamates 125 instead of O-allyl oxime
ether 128 to afford the corresponding isoxazoles 126 along with N-
allylisoxazolones 127. The formation of N-allylisoxazolones
increased as the R groups became bulkier.
Blum et al.42 reported intramolecular BAO r-bond additions
to the CAC triple bond to form 4-borylated isoxazoles 133,
which are potential building blocks for further functionalization
(Scheme 34). The reaction proceeded with gold catalysts at 50
°C or without catalyst at 110 °C, yielding a single regioisomer.
The utility of this reaction was extended for the scaled-up syn-
thesis of valdecoxib and a valdecoxib analog, a nonsteroidal
anti-inflammatory drug.
Ferreira et al.43 developed the regioisomeric synthesis of 3,5-
disubstituted isoxazoles 137 and 138 from propargylic N-hydroxy-
lamines 134 and propargylic amino ethers 135 via a Pt-catalyzed
cyclization (Scheme 35). The reaction mechanism involves the
intramolecular nucleophilic attack of oxygen or nitrogen to the
Pt-activated alkyne moiety. The 1,2-H shift, isomerization, and R3
group cleavage for aromatization yields the corresponding isoxa-
zoles. The authors extended this methodology for the synthesis
of anti-rhinovirus analogs.
Scheme 32. Synthesis of alkoxymethyl groups containing isoxazoles 124.
Scheme 33. Gold-catalyzed synthesis of 3-hydroxyisoxazoles 126.
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171 1167

Scheme 34. Synthesis of 4-borylated isoxazoles 133 via Au catalysis.

Scheme 35. Pt-catalyzed synthesis of regioisomeric isoxazoles 137 and 138.

Scheme 37. Synthesis of isoxazoles 143 from tert-butyl nitrite (142) and aryl
alkynes 141.

with a-bromonitrile were useful substrates for the synthesis of

5-aminoisoxazoles 140 (Scheme 36). The reaction mechanism
involves the conversion of the nitro group into oxime followed
by addition to the nitrile group to yield the corresponding 5-
amionoxazoles.

Scheme 36. Synthesis of 2-aminoisoxazoles 140.

Intramolecular nitro group addition to unsaturated CC bonds

Isoxazoles have also been prepared from intramolecularly the

addition of nitro or nitrite groups to the unsaturated CAC bonds,
as well as C@N and C@O groups. It should be noted that the mecha-
nisms of some such reactions are similar to those described in the
1,3-dipolar cycloaddition section. All recent methods for the synthe-
sis of isoxazoles, mostly via radical mechanisms, are covered here.
Watson et al.44 demonstrated that the b-cyanonitroalkanes 139
prepared from the copper-catalyzed alkylation of nitroalkanes Scheme 38. TEMPO-catalyzed synthesis of 5-substituted isoxazoles 144.
1168 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 39. Copper nitrite-mediated synthesis of isoxazoles 152.
Scheme 40. Synthesis of 3,4,5-trisubstituted isoxazoles 154a from MBH acetates by
an NaNO2/I2-mediated domino process.
Patel et al.45 reported the synthesis of 3,5-disubstituted isoxa-
zoles 143 from aryl alkynes 141 via a radical-mediated domino
process (formation of CAC, CAO, C@N, and C@O) (Scheme 37).
The 18O-labeled study revealed that the reaction mechanism
involved the cleavage of tert-butyl nitrite into a NO radical that
then oxidized to an NO2 radical. The sequential addition of these
radicals to styrene produced 2-nitroacetophenone. 2-Nitroace-
tophenone serves as a 1,3-dipolar intermediate for cycloaddition
with the second aryl alkene equivalent in presence of Sc(OTf)3 to
afford the corresponding 3,5-disubstituted isoxazole.
Pan et al.46 developed the 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO)-catalyzed synthesis of 5-substituted isoxazole 144 from
propargylic ketone 87a and TMSN3 (Scheme 38). TMSN3 was used
as a nitrogen source and reacted with TEMPO to generate an azido
radical. The addition of azido radical to alkyne and intramolecular
Scheme 41. Synthesis of isoxazoline N-oxides 163 and isoxazoles 165.
azide–alkene cycloaddition yields triazole 148. The triazole subse-
quently undergoes homolytic cleavage to give imine radical 149.
Finally, single-electron transfer followed by intramolecular radical
coupling provides the isoxazoles.
Xu et al.47 reported the synthesis of isoxazoles 152 via a copper
nitrite-catalyzed annulation reaction of two different alkynes in a
chemo and regioselective manner under controlled addition condi-
tions (Scheme 39). This method provided excellent yields and had
a broad scope of substrates that tolerated many different func-
tional groups.
Batra et al.48 reported the one-pot synthesis of 3,4,5-trisubsti-
tuted isoxazole 154a by using Morita–Baylis–Hillman (MBH) acet-
ate 153 in the presence of NaNO2 and I2 (Scheme 40). The
transformation involves the Michael addition of NaNO2 to the
MBH acetate to provide the allyl nitro intermediate 155, which
would then cause the I2-catalyzed oxidative a-CAH activation of
the nitromethyl subunit. The nucleophilic addition of a second
nitrite ion followed by [3+2] cycloaddition provides the 3-
nitroisoxazoles. The utility of 3-nitroisoxazoles for preparing func-
tionally diverse isoxazoles through SNAr reactions was also
demonstrated.
The divergent synthesis of trisubstituted isoxazoline N-oxides
163, dihydroisoxazoles 164, and isoxazoles 165 from aldehydes
and ethyl nitroacetate 162 was reported by Tanyeli et al.49
(Scheme 41). Temperature control was essential for product selec-
tivity: isoxazoline N-oxides 163 were obtained at 40 °C, whereas
isoxazoles 165 were obtained at 80 °C from aromatic aldehydes.
However, dihydroisoxazoles 164 were obtained as the major pro-
duct, along with isoxazoline N-oxides, from aliphatic aldehydes
at 40 °C.
Direct functionalization
The isoxazole ring is labile under basic conditions; thus, the
direct functionalization of isoxazoles at the C-3, C-4, and C-5 posi-
tions using transition metal-catalyzed cross-coupling and/or CAH
activation processes have received considerable attention. In this
chapter, we cover the recent advances in the transition metal-cat-
alyzed direct functionalizations of isoxazoles and fluorine-incorpo-
ration methods.
Scheme 42. AuCl(Pyc)-catalyzed oxidative C-4 selective CAH arylation of isoxa-
zoles 34 with arylsilanes 166.
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 43. Synthesis of tricyclic isoxazoles 172 from hydroximoyl chloride 1 and
terminal alkynes 170 through 1,3-dipolar cycloaddition followed by Pd(II)-cat-
alyzed intramolecular CAH arylation.
Scheme 44. C-3 functionalization of isoxazoles 174 via a Pd-catalyzed Suzuki–
Miyaura cross-coupling reaction.
Scheme 45. Pd-catalyzed Negishi coupling of isoxazole zinc pivalates 176.
Itami et al.50 developed a pyridylidene ligand-assisted, gold-cat-
alyzed, oxidative, C-4 selective CAH arylation of isoxazoles 34 with
arylsilanes 166 to provide 4-arylisoxazoles 167 in moderate yields
(Scheme 42). The highly electron-donating Pyc ligand acts as a new
type of non-classical N-heterocyclic carbine and is essential both to
oxidize the gold(I) to gold(III) and to stabilize the gold(III) species
for oxidative coupling. Along with the isoxazole coupling product,
4,40 -dibromobiphenyl (168) was obtained from the homocoupling
of the arylsilane and a significant amount of methyl 2-iodoben-
zoate (169) from isobutyl acrylate (IBA) esterification with MeOH.
Scheme 46. Direct CAH arylation of isoxazoles 179 at the C-5 position.
1169
Intramolecular CAH arylation at the C-4 position of isoxazoles
171 was catalyzed by Pd(II) to provide fused tricyclic isoxazoles
(Scheme 43).51 Although isoxazoles 171 were prepared from
propargyl phenyl ethers 170 through a sequential copper-cat-
alyzed 1,3-dipolar cycloaddition with hydroxymoyl chloride, the
direct transformation from 170 to the fused isoxazoles 172 also
proceeded via a tandem/cascade process in the presence of Pd(II)
catalysts.
Lipshutz et al.52 demonstrated the palladium-catalyzed Suzuki–
Miyaura cross-coupling reaction of aryl halides 174 with aryl/
hetaryl boron substrates 173 under very mild reaction conditions
with extremely low catalyst loadings (1000 ppm). The aqueous
reaction conditions make the reaction very useful for CAC bond
formation. The 1:1 combination of Pd(OAc)2 and HandaPhos with
a third-generation sterol-based surfactant, Nok, enabled the func-
tionalization of the isoxazoles at the C-3 position in excellent
yields (Scheme 44).
Alternatively, the Negishi cross-coupling of a variety of
organozinc pivalates, including isoxazole zinc pivalate 176, with
densely functionalized bromopyridine 177 proceeded in the pres-
ence of XPhos Pd G3 catalyst to provide drug-like molecules 178
(Scheme 45). The solid organozinc pivalates after solvent evapora-
tion were air and moisture stable compared to other RZnX
reagents; thus, their reactivities could be evaluated using high-
throughput experimentation protocols.53
Sasai et al.54 developed a direct CAH arylation of various 3-sub-
stituted and 3,4-disubstituted isoxazoles 179 (Scheme 46). The use
of 1,2-bis(diphenylphosphino)benzene (dppBz) enabled the intro-
duction of various aryl iodides into the C-5 position of the isoxa-
zoles; however, the direct CAH arylation of 3-unsubstituted
isoxazoles was not reported.
Our research group established a method to generate the
4-isoxazolyl anion species for the direct functionalization of
unsubstituted isoxazole. The microwave-irradiated 4-iodination
of isoxazole and a halogen-metal exchange reaction using a turbo
Grignard reagent (i-PrMgClLiCl) are essential for the generation
of 4-isoxazolyl anion species 182. This species could then be
reacted with various electrophiles to provide the corresponding
4-functionalized isoxazoles 183a–m (Scheme 47).55 This transfor-
mation enabled us to synthesize multiple functionalized isoxazoles
by introducing each substituent into the desired positions
individually.56
Scheme 47. Direct functionalization of isoxazole through the generation of 4-
isoxazolyl anion species 182.
1170 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171
Scheme 48. Decarboxylative fluorination of isoxazole carboxylic acids.
Scheme 49. Direct fluorination of isoxazoles 34 at the C-4 position.
Scheme 50. Difluoromethylthiolation of 5-aminoisoxazoles 187a and 187b.
Scheme 51. Trifluoroethylation of 3-acetylamideisoxazole 191.
Several incorporation methods of fluorine into isoxazoles 185
have been reported. Tang et al.57 developed a decarboxylative flu-
orination of isoxazole carboxylic acid 184 by using SelectfluorTM
(Scheme 48).
The direct fluorination of isoxazoles at the C-4 position was also
demonstrated by Sato et al.58 3,5-Disubstituted isoxazoles under-
went fluorination with SelectfluorTM to afford the corresponding
3,5-disubstituted 4-fluoroisoxazoles 186 in moderate yields
(Scheme 49). The use of excess SelectfluorTM gave 4,4,5-trifluo-
roisoxazolines 187.
Shen et al.59 developed a new electrophilic difluoromethylthio-
lating reagent, N-diflouoromethylthiophthalimide 188, which was
easily prepared in four steps from readily available pthalimide
and TMSCF2H. Reagent 188 was not found to be air and light sen-
sitive; therefore, it has a long shelf-life. This reagent enables the
difluoromethylthiolation of electronic rich heterocycles, including
5-aminoisoxazole 187a, under mild reaction conditions
(Scheme 50, Eq. (1)). Furthermore, the difluoromethylthiolation
also proceeded with HF2CSO2Na in the presence of Ph2PCl and
TMSCl. The generated SCF3H species 190 is the potential reactive
species that reacts with phenols and related heterocycles, includ-
ing 5-aminoisoxazole 187b (Scheme 50, Eq. (2)).60
Novak et al.61 reported the direct Pd-catalyzed trifluoroethyla-
tion of aromatic compounds using mesityl(trifluoroethyl)iodonium
salt 192 via CAH activation. The acetamide group is necessary as a
directing group to activate the a-CAH bond. Indeed, 3-acety-
lamideisoxazole 191 underwent trifluoroethylation at the C-4 posi-
tion and the double bond was isomerized to the exo product 193
(Scheme 51).
Conclusion
We have summarized the recent synthetic advances for func-
tionalized isoxazoles over the last three years. The synthetic
approach toward functionalized isoxazoles via the 1,3-dipolar
cycloaddition of nitrile oxides to alkynes is a well-established
route; nevertheless, the recent advances (aqueous reaction condi-
tions) in this reaction class enable applications to bioconjugation
in chemical biology. Various direct functionalization methods have
also been developed under neutral conditions by using transition
metal catalysts, such as palladium and gold, to avoid the handling
of isoxazoles under highly basic conditions. Furthermore, driven by
the biological importance of fluorinated compounds, several fluo-
rine-incorporation-into-isoxazole methods have been developed.
Given that isoxazole is a key pharmacophore critical to biological
activity, we are now in a position to synthesize more complex,
multifunctional isoxazoles.
Acknowledgment
This research is partially supported by the Japan Society for the
Promotion of Science (JSPS, ID No. 17J02929).
References
1. (a) Taylor RD, MacCoss M, Lawson ADG. J Med Chem. 2014;57:5845–5859;
(b) Hu F, Szostak M. Adv Synth Catal. 2015;357:583–2614.
2. Fouli FA, Habashy MM, El-Kafrawy AF, Youseef ASA, El-Adly MM. J Prakt Chem.
1987;329:1116–1122.
3. Hansen TV, Wu P, Fokin VV. J Org Chem. 2005;70:7761–7764.
4. Poh J-S, Garcia-Ruiz C, Zúñiga A, et al. Org Biomol Chem. 2016;14:5983–5991.
5. Khutorianskyi A, Chalyk B, Borysko P, Kondratiuk A, Mykhailiuk PK. Eur J Org
Chem. 2017;3935–3940.
6. Guo Y, Wang X, Zhu Z, Zhang J, Wu Y. Synlett. 2016;27:2259–2263.
7. Chen W, Zhang J, Wang B, Zhao Z, Wang X, Hu Y. J Org Chem.
2015;80:2413–2417.
8. Das P, Omollo AO, Sitole LJ, et al. Tetrahedron Lett. 2015;56:1794–1797.
9. Kesornpun C, Aree T, Mahidol C, Ruchirawat S, Kittakoop P. Angew Chem Int Ed.
2016;55:3997–4001.
10. Reja RM, Sunny S, Gopi HN. Org Lett. 2017;19:3572–3575.
11. Okusu S, Tokunaga E, Shibata N. Org Lett. 2015;17:3802–3805.
12. Kuribayashi S, Shida N, Inagi S, Fuchigami T. Tetrahedron. 2016;72:5343–5349.
13. Zhou X, Xu X, Shi Z, Liu K, Gao H, Li W. Org Biomol Chem. 2016;14:5246–5250.
14. Kankala S, Jonnalagadda SB, Vasam CS. RSC Adv. 2015;5:76582–76587.
15. Kadam KS, Gandhi T, Gupte A, Gangopadhyay AK, Sharma R. Synthesis.
2016;48:3996–4008.
16. Sanders BC, Friscourt F, Ledin PA, et al. J Am Chem Soc. 2011;133:949–957.
17. Singhal A, Parumala SKR, Sharma A, Peddinti RK. Tetrahedron Lett.
2016;57:719–722.
18. Kondacs LA, Pilipecz MV, Musci Z, et al. Eur J Org Chem. 2015;6872–6890.
19. Wang G-W, Cheng M-X, Ma R-S, Yang S-D. Chem Commun. 2015;51:6308–6311.
20. Iwai K, Asahara H, Nishiwaki N. J Org Chem. 2017;82:5409–5415.
21. Dang TT, Albrecht U, Langer P. Synthesis. 2006;2515–2522.
22. Ngo TN, Ejaz SA, Hung TQ, et al. Org Biomol Chem. 2015;13:8277–8290.
23. Schmitt E, Rugeri B, Panossian A, Vors J-P, Pazenok S, Leroux FR. Org Lett.
2015;17:4510–4513.
24. Schmitt E, Bouvet S, Pégot B, et al. Org Lett. 2017;19:4960–4963.
25. Li J, Ma W, Ming W, Xu C, Wei N, Wang M. J Org Chem. 2015;80:11138–11142.
26. Wang Q, Lou J, Wu P, Wu K, Yu Z. Adv Synth Catal. 2017;359:2981–2998.
27. Yao X, Wang T, Zhang X, et al. Adv Synth Catal. 2016;358:1534–1539.
 T. Morita et al. / Tetrahedron Letters 59 (2018) 1159–1171 1171

28. Kumar GR, Kumar YK, Reddy MS. Chem Commun. 2016;52:6589–6592. 43. Allegretti PA, Ferreira EM. Chem Sci. 2013;4:1053–1058.
29. Andreev MV, Medvedeva AS, Larina LL, Demina MM. Mendeleev Commun. 44. Shimkin KW, Gildner PG, Watson DA. Org Lett. 2016;18:988–991.
2017;27:175–177. 45. Sau P, Santra SK, Rakshit A, Patel BK. J Org Chem. 2017;82:6358–6365.
30. Wang L, Yu X, Feng X, Bao M. Org Lett. 2012;14:2418–2421. 46. He Y, Xie Y-Y, Wang Y-C, et al. RSC Adv. 2016;6:58988–58993.
31. Shen R, Yang J, Luo B, Zhang L, Han L-B. Adv Synth Catal. 2016;358:3897–3906. 47. Li Y, Gao M, Liu B, Xu B. Org Chem Front. 2017;4:445–449.
32. Zheng J, Chen Q-Y, Sun K, Huang Y, Guo Y. Tetrahedron Lett. 48. Dighe SU, Mukopadhyay S, Kolle S, Kanojiya S, Batra S. Angew Chem Int Ed.
2016;57:5757–5760. 2015;54:10926–10930.
33. Bondarenko OB, Vinogradov AA, Danilov PA, Nikolaeva SN, Gavrilova AY, Zyk 49. Rouf A, Sahin E, Tanyeli C. Tetrahedron. 2017;73:331–337.
NV. Tetrahedron Lett. 2015;56:6577–6579. 50. Hata K, Ito H, Segawa Y, Itami K. Beilstein J Org Chem. 2015;11:2737–2746.
34. Xue S, Liu J, Wang C. Eur J Org Chem. 2016;2450–2456. 51. Guo D-C, Zhang C, Li F, Zhang F, Yu F, He Y-P. Synthesis. 2017;49:1356–1370.
35. Tost BM. Acc Chem Res. 2002;35:695–705. 52. Handa S, Andersson MP, Gallou F, Reilly J, Lipshutz BH. Angew Chem Int Ed.
36. Nakamura I, Gima S, Kudo Y, Terada M. Angew Chem Int Ed. 2016;55:4914–4918.
2015;54:7154–7157. 53. Greshock TJ, Moore KP, McClain RT, et al. Angew Chem Int Ed.
37. Gima S, Nakamura I, Terada M. Eur J Org Chem. 2017;4375–4378. 2016;55:13714–13718.
38. Kaewsri W, Thongsornkleeb C, Tummatorn J, Ruchirawat S. RSC Adv. 54. Shigenobu M, Takenaka K, Sasai H. Angew Chem Int Ed. 2015;54:9572–9576.
2016;6:48666–48675. 55. Morita T, Fuse S, Nakamura H. Angew Chem Int Ed. 2016;55:13580–13584.
39. Jonusis M, Steinys L, Buksnaitiene R, Cikotiene I. Synthesis. 2017;49:1122–1130. 56. Fuse S, Morita T, Nakamura H. Synthesis. 2017;49:2351–2360.
40. Sugita S, Ueda M, Doi N, Takeda N, Miyata O. Tetrahedron Lett. 57. Yuan X, Yao J-F, Tang Z-Y. Org Lett. 2015;17:4510–4513.
2016;57:1786–1789. 58. Sato K, Sandford G, Shimizu K, et al. Tetrahedron. 2016;72:1690–1698.
41. Ueda M, Sato A, Ikeda Y, Miyoshi T, Naito T, Miyata O. Org Lett. 59. Zhu D, Gu Y, Lu L, Shen Q. J Am Chem Soc. 2015;137:10547–10553.
2010;12:2594–2597. 60. Huang Z, Matsubara O, Jia S, Tokunaga E, Shibata N. Org Lett. 2017;19:934–937.
42. Tu KN, Hirner JJ, Blum SA. Org Lett. 2016;18:480–483. 61. Toth B, Kovacs S, Salyi G, Novak Z. Angew Chem Int Ed. 2016;55:1988–1992.