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Recent Progresses in the Synthesis of Functionalized Isoxazoles

Taiki Morita, Somaraju Yugandar, Shinichiro Fuse, Hiroyuki Nakamura

PII: S0040-4039(18)30187-4
DOI: https://doi.org/10.1016/j.tetlet.2018.02.020
Reference: TETL 49705

To appear in: Tetrahedron Letters

Received Date: 27 December 2017

Revised Date: 7 February 2018
Accepted Date: 8 February 2018

Please cite this article as: Morita, T., Yugandar, S., Fuse, S., Nakamura, H., Recent Progresses in the Synthesis of
Functionalized Isoxazoles, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.02.020

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Graphical Abstract

Recent Progress in the Synthesis of Leave this area blank for abstract info.
Functionalized Isoxazoles
Taiki Morita, Somaraju Yugandar, Shinichiro Fuse, Hiroyuki Nakamura*
 1

Tetrahedron Letters
j o ur n al h o m e p a g e : w w w . e l s e v i e r . c o m

Recent Progresses in the Synthesis of Functionalized Isoxazoles

Taiki Moritaa, Somaraju Yugandara, Shinichiro Fusea, Hiroyuki Nakamuraa*
a
Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho Midori-ku, Yokohama 226-
8503, Japan

AR T IC LE IN F O A B S TR A C T

Article history: Isoxazole is an important pharmacophore that is critical for biological activity. The isoxazole ring
Received ranks 33rd in frequency among the 351 ring systems found in marketed drugs, thus suggesting a
Received in revised form great deal of interest in the synthesis of functional isoxazoles. In recent years, various approaches
Accepted have been developed for the synthesis and functionalization of isoxazoles. This comprehensive
Available online survey summarizes the 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
Keywords: cycloaddition, (2) condensation, (3) cycloisomerization, and (4) direct functionalization.
Isoxazole 2009 Elsevier Ltd. All rights reserved.
cycloaddition
condensation
cycloisomerization
functionalization

Contents

Introduction
Cycloaddition
Condensation
Cycloisomerization
Direct functionalization
Conclusion
Acknowledgment
References

Introduction (1) 1,3-Dipolar Cycloaddition (2) Condensation

R1 N O HO
Isoxazole is a five-membered heteroaromatic ring that N O
contains contiguous nitrogen and oxygen atoms. It is an N O R1 R3
R2 R3
important framework and a critical pharmacophore for biological R1 3 5 R
3 R2
4
activity. The isoxazole ring has desirable pharmacological (3) Cycloisomerization R2 (4) Direct Fuctionalization
activity because its two contiguous electronegative heteroatoms Functionalized
contribute to hydrogen donor–acceptor interactions, with various HO
N
Isoxazoles
N O
target enzymes and receptors inaccessible by other ring systems.
R1
Indeed, the isoxazole ring ranks 33rd in frequency among the 351 R
R3
ring systems found in currently marketed drugs, thus suggesting a
Figure 1. Synthetic approaches of functionalized isoxazoles. 1b
great deal of interest in the synthesis of functional isoxazoles.1
In recent years, various approaches have been developed for In this summary, a comprehensive survey of recent progress in
the synthesis and functionalization of isoxazoles. They have been the synthesis of functionalized isoxazoles, particularly over the
summarized in several authoritative reviews. Especially notable last three years, is presented. The review discusses new synthetic
is the comprehensive review published by Hu and Szostak1b in approaches to functionalized isoxazoles based on the following
2015 on the synthesis, reaction mechanisms, and reactivity of four reaction types: (1) 1,3-dipolar cycloaddition, (2)
isoxazoles, including synthetically useful metal-catalyzed condensation, (3) cycloisomerization, and (4) direct
reactions. functionalization.
2 Tetrahedron
1,3-Dipolar cycloaddition block for further functionalization at the C4 position (Scheme 3).
The proposed isoxazole ring construction of the mechanistic
One of the best established routes to isoxazole synthesis is the studies did not occur through 1,3-dipolar cycloaddition; however,
1,3-dipolar cycloaddition of nitrile oxides to alkynes/alkenes. a stepwise bond formation mechanism was invoked. The
The reaction of nitrile oxides with alkynes proceeds under resulting intermediate reacted with N-iodosuccinimide (NIS) to
thermal conditions; however, the regioselectivity is very poor install iodine at the C-4 position of the isoxazoles 9. By contrast,
because of the high activation energy to the reaction. 2 Fokin et 3-chloro-4-iodoisoxazoles were synthesized from
al.3 reported a copper-catalyzed 1,3-dipolar cycloaddition of dichloroaldoxime 1c (Scheme 4).7 The use of copper acetylide
alkynes with nitrile oxides generated from oxime halides under was the key to preventing the dimerization of the nitrile oxide.
basic conditions in 2005. This strategy enabled the synthesis of The combination of alkynylcopper(I) and molecular iodine was
functionalized isoxazoles in high yields and regioselectivities used as a synthetic equivalent to 1-iodoalkyne. The triple bond of
under mild conditions. Nowadays, both metal-catalyzed and 1-iodoalkyne was activated by coordination to CuI and reacted
metal-free 1,3-dipolar cycloadditions have been developed under with α-chloronitrile oxide to yield 3-chloro-4-iodoisoxazoles 11
mild conditions to access functionalized isoxazoles. as a novel building block with a broad substrate scope.
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-trifluoromethylisoxazoles. They prepared
hydroximoyl bromide 1a as a precursor to nitrile oxide 2a from a
commercially available trifluoromethylated hemiacetal in two
steps. Bromide 1a was readily converted into the corresponding
nitrile oxide under basic conditions for reacting with terminal
alkynes to yield the corresponding 3-trifluoromethyl-5-
substituted isoxazoles 3 in good to high yields (Scheme 1). The
combination of base/solvent affected the 1,3-dipolar
cycloaddition yields greatly: trimethylamine/toluene was suitable
for aromatic alkynes, whereas Na2 CO3/H2O was suitable for
aliphatic alkynes. Furthermore, difluoromethyl-substituted
isoxazoles were synthesized through the 1,3-dipolar
cycloaddition of difluoromethyl nitrile oxides generated from Scheme 3. One-pot synthesis of 3-trifluoromethyl-4-iodoisoxazole 7.
oxime 4a to alkynes and enamines (Scheme 2). 5

Scheme 1. Synthesis of 3-trifluoromethylisoxazoles 3 using hydroximoyl

bromide 1a.

R N O
F
R Scheme 4. One-pot synthesis of 3-chloro-4-iodo isoxazoles 11.
NOH NCS F
O 5
F F N
CHCl3, rt N O Hamme II et al.8 prepared a series of 4-bromo spiro-
F F F
isoxazolines 14 containing various aliphatic and aromatic
4a 2b R
NR'2
F R substituents at the 3-position via 1,3-dipolar cycloaddition
6 followed by the intramolecular cyclization of a pendant hydroxyl
N O N O N O or carboxylic acid group (Scheme 5). Among these molecules,
F F OH F compound 14a showed the most prominent anti-cancer activity
CO2Et O
F F F BocN toward breast cancer cell lines MCF-7 and MDA-MB-231, with
5a, 73% 5b, 67% 5c, 48% IC50 values of 52.4 and 43.1 µM, respectively.
OH
R1 N
N O N O N O X OH R
F F F Cl
N Br3 R1
R1 O N
n R R1 H O
F CO2Et F CN F X X
O R1 R
NEt3, CH2Cl2 N OH K2CO3, CH2Cl2 Br R1
6a, 80% 6b, 34% 6c,47% n
O n
12 13 Cl 14
Scheme 2. Synthesis of 3-difluoromethyl isoxazoles 6. n = 1, 2
O
O N 16 examples
X = H2, O (61-80%)

Br Cl
The one-pot synthesis of 3-trifluoromethyl-4-iodoisoxazoles 14a
from trifluoromethylated oxime 1b and alkynes was
demonstrated by Wu et al.6 The reaction of 1b with Scheme 5. Synthesis of furan, pyran, and lactone containing spiro-
phenylacetylene proceeded at room temperature to afford 4-iodo- isoxazolines 14.
5-phenyl-3-(trifluoromethyl)isoxazole (7), a useful building

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 peptides. 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 presence of copper catalysts to afford
double-conjugated peptide 18 (Scheme 7).
3
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 4-difluoromethyl isoxazoles 20 (Scheme 8).
Electrochemical fluorination is also useful for the synthesis of
partially fluorinated terminal 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).

0.1 M phosphate buffer (10.0 mL)

NOH N O
R3
+
R 1
Cl R1 R3
R2 acetone (0.5 mL), pH 4.0, rt 2
1 R
1.2 mmol 1.0 mmol 15
Scheme 8. Synthesis of 4-difluoromethyl isoxazoles 20.
N O N O N O NOH
EtO2C CO 2H CO2Et F X N O
Cl HF salt Ph Cl SR
H Cl Cl H SR SR Ph
H +
21
-2ne, -nH
22 2 mol% CuSO4· 5H 2O 23 F X
15a, 44% 15b, 67% 15c,50% sodium ascorbate
DME X = F or H
N O N O 9 examples KHCO3
20-77% t-BuOH/H2O (1:1), rt
CO2 Me
Br Cl Selected Examples
Me CO2Et
15d, 69% 15e, 58% N O N O N N O O
S Ph S S
Ph Ph Ph
N O N O F F N N N
F F
EtO2 C 23a , 35% 23b, 35% 23c , 72%
n
Pr O2N n
Pr
15f, 8% 15g, 8% Scheme 9. Electrochemical fluorination of propargylic thioethers 21.

Organocatalysts can also be used to induce the 1,3-dipolar

Scheme 6. Generation of nitrile oxide in aqueous solutions.
cycloaddition of nitrile oxides with β -functionalized ketones 24
to synthesize 3,4,5-trisubstituted isoxazoles (Scheme 10). In this
transformation, organocatalyst 1,1,3,3-tetramethylguanidine
(TMG) was reacted with β-keto amides to generate enolates that
could undergo 1,3-dipolar cycloaddition with nitrile oxide to
afford the corresponding isoxazoles 25.13

20 mol% TMG N O
O NOH NH
+ R3 R1 26 examples
1 R2 3
R R Cl NEt 3, MeOH N N
80 °C, 48 h R2 O
24 1 25 TMG

Selected Examples
Br
N O N O N O N O N O
Ph Me Me Me Ph Ph Ph

PhHN O PhHN O PhHN O PhHN O Ph O

25a , 76% 25b, 76% 25c, 93% 25d, 72% 25e , 54%

Scheme 10. Organocatalyst-induced 1,3-dipolar cycloaddition of

hydroximoyl chloride 1 with β -functionalized ketones 24.

In addition to enolates, allenyl Grignard reagent 26 underwent

Scheme 7. Orthogonal cycloadditions using azide and nitro group.
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)isoxazole 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
4 Tetrahedron
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.

Scheme 13. Generation of nitrile oxide from aldoxime 4a using PhI(OAc)2.

Nitroso-nitro enamine 39 was also used as a nitrile oxide

precursor. The nitroso-nitro enamine was prepared from 2-
(nitromethylene)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 isoxazoles 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 generated by the elimination of a nitro group
Scheme 11. NHC-catalyzed domino addition of allenyl Grignard reagent 26 as HNO2. The isoxazoles generated by the cycloaddition of nitrile
to nitrile oxide 2c. oxide 43 with alkynes result in two isomers due to
tautomerization. The enamine form 45 would trap a nitronium
ion to afford isoxazoles 40.
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 generated, along with the
formation of nitrile oxide. This in-situ formed nitrile oxide could
react with alkynes to afford 3,5-disubstituted isoxazoles in a one-
pot procedure (Scheme 12).15 Hypervalent 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 acetate 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

Scheme 14. Generation of nitrile oxide from nitroso-nitro enamine 39 for the
synthesis of isoxazoles.

Another interesting approach toward the generation of nitrile

Scheme 12. Generation of nitrile oxide 2 using isoamyl nitrite 33.
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 NO3- followed by the
elimination of 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.
 5
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-trifluoromethyl
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-trifluoromethyl isoxazoles 67.

O
n-BuLi
OH (2.2 equiv. ) OLi EtO CF3
N N N O OLi
THF Li Ar CF 3
Ar Ar -78 °C to 20 °C
-78 °C to 20 °C
64 65 66
TFA
reflux
N O
Ar = 4-OMeC6H 4 : 57%
Scheme 15. Copper-catalyzed synthesis of isoxazoles 48 from 2- Ar = 2-Naphthyl : 62% Ar CF 3
ethylazaarene 47. 67

Scheme 17. One-pot synthesis of 5-trifluoromethyl isoxazoles 67.

20
Nishiwaki et al. developed novel dianionic reagent 57 from
The development of novel 1,3-dicarbonyl equivalents enables
the pyridium salt of nitroisoxazolone 56 to synthesize 3-cyano-5-
easy accesses to highly functionalized isoxazoles. Leroux et al.23
acylisoxazoles (Scheme 16). In this reaction, dianionic reagent 57
succeeded in the preparation of fluorinated iminium salt 69 from
serves as a masked version of highly explosive nitro-acetonitrile.
commercially available 1,1,2,2-tetrafluoro-N,N-dimethylethan-1-
The first step is considered the decarboxylation/Michael addition
amine (68). The iminium salt 69 was trapped with ethyl
of 57 to enone 58 to produce intermediate 60. Thereafter,
cyanoacetate or malononitrile to give the corresponding
cyclization forms isoxazoline 61. A subsequent proton transfer
enaminones. The reaction of these enaminones with hydroxyl
yields 63, and dehydration furnishes the final product 59. In the
amine resulted in highly functionalized isoxazoles 71
other possible mechanistic pathway, 60 would undergo the
quantitatively (Scheme 18). Furthermore,
elimination of hydrochloric acid (HCl) to afford enone 62. The
fluoro(trifluoromethoxy)methyl-substituted isoxazoles 76 were
subsequent cyclization would lead to isoxazoline 63.
synthesized from commercially available trifluoromethyl
trifluorovinyl ether (72) (Scheme 19).24 The key aspect of this
transformation is the preparation of fluoro(trifluoromethoxy)
iminium salt 74 from trifluoromethyl trifluorovinyl ether (72).
Perfluorinated isoxazoles 76 were obtained in a similar manner to
the protocol described in Scheme 18.

Scheme 16. Synthesis of 5-acyl-3-cyanoisoxazoles 59.

Condensation reactions using 1,3-dicarbonyl derivatives

Another frequently invested approach to isoxazoles is the
condensation reaction of hydroxylamine with 1,3-dicarbonyl Scheme 18. Synthesis of 3-difluoromethyl isoxazoles 71 from fluorinated
compounds or its equivalents, such as α,β -unsaturated carbonyl iminium salt 69.
compounds. In this approach, the isoxazole ring is constructed
from a three-carbon unit and a small component possessing a N–
O 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
6 Tetrahedron

Scheme 19. Synthesis of 3-fluoro(trifluoromethoxy)methyl isoxazoles 76

using perfluorinated iminium salt 74.

β –Oxodithioesters have also been used as 1,3-dicarbonyl

derivatives to synthesize 3-methylthio-isoxazoles. Various 3-
methylthio-5-aryl-isoxazoles 78 were synthesized from β–
oxodithioesters with hydroxylamine under acidic conditions
(Scheme 20).25 The use of HOAc as a solvent is essential for
isoxazole ring formation: β -ketonitriles were obtained when the
reaction was performed in ethanol. By contrast, 5-methylthio
isoxazoles 80 were obtained from the reaction of α-oxo ketene
dithioacetals 79 with hydroxylamine under basic conditions
(Scheme 21). 26
. with hydroxylamine or its equivalents to synthesize isoxazoles.
Scheme 20. Synthesis of 3-methylthio isoxazoles 78 from β–oxo dithioesters
77.
Scheme 22. One-pot synthesis of isoxazoles 82 via tandem oxidation/1,2-
migration of propargyl alcohol 81.
Ynones are conventionally used as 1,3-dicarbonyl derivatives
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 oxygen enables a syn-Michael addition to
the carbonyl group, thus generating vinyl azide 89. Two
pathways were proposed for isoxazole formation: direct
cyclization releasing nitrogen gas or formation 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.

Scheme 21. Synthesis of 5-methylthio isoxazoles 80 from α-oxo ketene

dithioacetals 79.

Zhang et al.27 reported a one-pot synthesis of trisubstituted

isoxazoles from tertiary propargyl alcohol 81 (Scheme 22). α -
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.

Scheme 23. Synthesis of 3,5-disubstituted isoxazoles 34 from ynones 87 and

TMSN3.
 7

Scheme 24. Synthesis of 5-aminoisoxazoles 92 from ynones 91 and sodium

azide.

Since Yu and Bao30 first reported the synthesis of 3,5-

disubstituted isoxazoles in 2012, variously functionalized diynes
have been employed for the mild intramolecular Cope-type Scheme 27. Synthesis of 5-bromoisoxazoles 102 from 1,1-
hydroamination of 1,3-dialkynes with hydroxylamine and dibromocyclopropanes 101.
subsequent electrophilic addition method. For example, Shen and
Han31 developed a copper-catalyzed synthesis of 1-phosphonyl
2,4-diynes and converted them to isoxazole-tethered phosphine
oxides 96a and 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-trifluoroethyl isoxazole 100 (Scheme 26),32
although the regioselectivity was not reported.

Scheme 28. DBU-mediated synthesis of fully substituted isoxazoles 106 from

electron-deficient cyclopropanes 105 and nitromethane.
Scheme 25. Synthesis of isoxazole-tethered phosphine oxides 96a and 96b
from 1-phosphonyl 2,4-diyne 95.
Cycloisomerization
CF 3
Cu
CF3 (2.0 equiv.) Cycloisomerization is a powerful method in terms of the
+ generation of intrinsic atom-economy structural complexity in
Cl Cl ethanolamine
97 98 Ph DCE, 75 °C, 75% 99 organic synthesis.35 In this section, we cover the recent advances
Ph
NH2OH·HCl Ph
in isoxazole synthesis via cycloisomerization under both metal-
NEt3
N O
catalyzed and metal-free conditions.
DMSO, 120 °C F 3C
51% Nakamura et al. 36 developed a skeletal rearrangement of O-
100
propargylic formaldoximes 112 in the presence of a gold catalyst
Scheme 26. Synthesis of 3-trifluoroethylisoxazole 100 using conjugated for the preparation of 4-methylenated isoxazoline derivatives 113
diyne 98. via a unique intermolecular methylene transfer pathway.
Thereafter, these isoxazolines underwent isomerization or an ene
Cyclopropanes can serve as a three-carbon unit for the reaction with maleimide, azodicarboxylate, and glyoxalate to
provide the corresponding functionalized isoxazoles114-117
synthesis of isoxazoles. Bondarenko et al.33 reported the
(Scheme 29). Furthermore, this system can be used for the
nitrosation of 2-aryl-1,1,-dibromocyclopropanes 101 to afford 5-
bromoisoxazoles (Scheme 27). The ring opening of cyclopropane synthesis of chiral isoxazole 120 from enantioenriched O-
is triggered by the nitrosonium ion to yield dibromocarbocation propargylic oxime 118 through chirality transfer (Scheme 30).37
103, which undergoes intramolecular cyclization followed by the Interestingly, the chirality of the enantioenriched O-propargylic
elimination of HBr to afford 5-bromoisoxazoles. Alternatively, oxime 118 was completely retained during the gold-catalyzed
nitromethane was used for the construction of isoxazoles through skeletal rearrangement/ene reaction cascade.
[3+2] cycloaddition 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 formal 1,3-dipolar cycloaddition with
nitromethane to yield the corresponding isoxazole-5-carboxylates
through 5-membered heterocyclic intermediates.
8 Tetrahedron
Scheme 29. Synthesis of 4-methylenated isoxazoline derivatives 113.
Scheme 30. Synthesis of enantioenriched isoxazole 120.
Thongsornkleeb et al.38 reported the synthesis of 4-
chloroisoxazole 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 (Cl 2) 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-bromosuccinimide and NIS.
Scheme 31. Intramolecular cyclization of (E/Z)-alkyl-O-methyl oximes to
isoxazoles 122.
Strong electrophiles, such as oxocarbenium cations, also
promote the intramolecular cyclization of alkynyl-O-methyl
oximes. 4-[Alkoxy(aryl)methyl]-substituted isoxazoles 124 were
synthesized 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 activating 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.
Scheme 32. Synthesis of alkoxymethyl groups containing isoxazoles 124.
Miyata and Ueda et al.40 reported the gold-catalyzed
sequential cyclization/[3,3]-sigmatropic rearrangements of O-
allyl hydroximates 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 hydroximates
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.
Scheme 33. Gold-catalyzed synthesis of 3-hydroxyisoxazoles 126.
Blum et al.42 reported intramolecular B–O σ-bond additions to
the C–C 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 synthesis of
valdecoxib and a valdecoxib analog, a nonsteroidal anti-
inflammatory drug
Scheme 34. Synthesis of 4-borylated isoxazoles 133 via Au catalysis.
Ferreira et al.43 developed the regioisomeric synthesis of 3,5-
disubstituted isoxazoles 137 and 138 from propargylic N-
hydroxylamines 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 isoxazoles. The authors extended this
methodology for the synthesis of anti-rhinovirus analogs.
 9

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

Intramolecular nitro group addition to unsaturated C-C

bonds
Isoxazoles have also been prepared from intramolecularly the
addition of nitro or nitrite groups to the unsaturated C–C bonds,
as well as C=N and C=O groups. It should be noted that the
mechanisms of some such reactions are similar to those described
in the 1,3-dipolar cycloaddition section. All recent methods for
the synthesis of isoxazoles, mostly via radical mechanisms, are
covered here.
Watson et al. 44 demonstrated that the β-cyanonitroalkanes 139
prepared from the copper-catalyzed alkylation of nitroalkanes
with α-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 37. Synthesis of isoxazoles 143 from tert-butyl nitrite (142) and aryl
alkynes 141.
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 azide–alkene cycloaddition yields triazole
148. The triazole subsequently undergoes homloytic cleavage to
give imine radical 149. Finally, single-electron transfer followed
by intramolecular radical coupling provides the isoxazoles.

Scheme 38. TEMPO-catalyzed synthesis of 5-substituted isoxazoles 144.

Xu et al. 47 reported the synthesis of isoxazoles 152 via a copper

Scheme 36. Synthesis of 2-aminoisoxazoles 140.
nitrite-catalyzed annulation reaction of two different alkynes in a
chemo and regioselective manner under controlled addition
conditions (Scheme 39). This method provided excellent yields
Patel et al.45 reported the synthesis of 3,5-disubstituted and had a high substrate scope that tolerated many different
isoxazoles 143 from aryl alkynes 141 via a radical-mediated functional groups.
domino process (formation of C–C, C–O, 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·. The sequential addition of
these radicals to styrene produced 2-nitroacetophenone. 2-
Nitroacetophenone 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.

Scheme 39. Copper nitrite-mediated synthesis of isoxazoles 152.

10 Tetrahedron
Batra et al.48 reported the one-pot synthesis of 3,4,5- positions using transition metal-catalyzed cross-coupling and/or
trisubstituted isoxazole 154a by using Morita–Baylis–Hillman C–H activation processes have received considerable attention. In
(MBH) acetate 153 in the presence of NaNO2 and I2 (Scheme this chapter, we cover the recent advances in the transition metal-
40). The transformation involves the Michael addition of NaNO2 catalyzed direct functionalizations of isoxazoles and fluorine-
to the MBH acetate to provide the allyl nitro intermediate 155, incorporation methods.
which would then cause the I2-catalyzed oxidative α-C–H
Itami et al.50 developed a pyridylidene ligand-assisted, gold-
activation of the nitromethyl subunit. The nucleophilic addition
catalyzed, oxidative, C-4 selective C–H arylation of isoxazoles
of a second nitrite ion followed by [3+2] cycloaddition provides
34 with arylsilanes 166 to provide 4-arylisoxazoles 167 in
the 3-nitroisoxazoles. The utility of 3-nitroisoxazoles for
moderate yields (Scheme 42). The highly electron-donating Pyc
preparing functionally diverse isoxazoles through SNAr reactions
ligand acts as a new type of non-classical N-heterocyclic carbine
was also demonstrated.
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, 4,4’-dibromobiphenyl (168) was
NaNO2 (2.0 equiv.)
OAc I2 (20 mol %) MeO2C NO2 obtained from the homocoupling of the arylsilane and a
CO2Me DMSO (5.0 equiv.) significant amount of methyl 2-iodobenzoate (169) from isobutyl
Ph N + 28 examples
DMF, rt, 3-8 h Ph O 98-68% acrylate (IBA) esterification with MeOH.
153 154a, 80%

Proposed mechanism

OAc
I2 EWG SET [O]
EWG EWG R
R R
AcONa HI
H NO2
NO2 DMSO
155 156
NaNO2 I2 + DMSO + H2O

EWG EWG NaNO2 EWG

R R H
R H
NO2 NO2 N NO2
H O O
157 158 159
EWG EWG NO2 EWG NO2
R [3+2]

O N NO2 cycloaddition R N OH H2O N

R
OH H O O

160 161 154

Scheme 40. Synthesis of 3,4,5-trisubstituted isoxazoles 154a from MBH

acetates by an NaNO2/I2-mediated domino process.

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
selectivity: 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 product, along with isoxazoline N-oxides, from aliphatic
aldehydes at 40 °C.
Scheme 42. AuCl(Pyc)-catalyzed oxidative C-4 selective C–H arylation of
isoxazoles 34 with arylsilanes 166.
Intramolecular C–H 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-
catalyzed 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.

Scheme 41. Synthesis of isoxazoline N-oxides 163 and isoxazoles 165.
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
Scheme 43. Synthesis of tricyclic isoxazoles 172 from hydroximoyl chloride
1 and terminal alkynes 170 through 1,3-dipolar cycloaddition followed by
Pd(II)-catalyzed intramolecular C–H arylation.
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
 11
conditions with extremely low catalyst loadings (≤1000 ppm). Our research group established a method to generate the 4-
The aqueous reaction conditions make the reaction very useful isoxazolyl anion species for the direct functionalization of
for C–C bond formation. The 1:1 combination of Pd(OAc)2 and unsubstituted isoxazole. The microwave-irradiated 4-iodination
HandaPhos with a third-generation sterol-based surfactant, Nok, of isoxazole and a halogen-metal exchange reaction using a turbo
enabled the functionalization of the isoxazoles at the C-3 position Grignard reagent (i-PrMgCl .LiCl) are essential for the generation
in excellent yields (Scheme 44). of 4-isoxazolyl anion species 182. This species could then be
1000 ppm
reacted with various electrophiles to provide the corresponding 4-
O
OEt
1:1 HandaPhos/Pd(OAc) 2 O
OEt
functionalized isoxazoles 183a–m (Scheme 47).55 This
B 0.14 mL Et3 N (2.0 equiv.)
Br Ph Ph transformation enabled us to synthesize multiple functionalized
+
N O
N 2 wt% Nok in H 2O
N O
N isoxazoles by introducing each substituent into the desired
Ph 0.5 M, rt, 24 h Ph
173 174 175
positions individually.56
i-Pr B = B(OH)2, 85%
O BF 3K, 87%
P
O O i-Pr i-Pr

HandaPhos

Scheme 44. C-3 functionalization of isoxazoles 174 via a Pd-catalyzed

Suzuki–Miyura cross-coupling reaction.

Alternatively, the Negishi cross-coupling of a variety of

organozinc pivalates, including isoxazole zinc pivalate 176, with
densely functionalized bromopyridine 177 proceeded in the
presence of XPhos Pd G3 catalyst to provide drug-like molecules
178 (Scheme 45). The solid organozinc pivalates after solvent
evaporation were air and moisture stable compared to other
RZnX reagents; thus, their reactivities could be evaluated using
high-throughput experimentation protocols.53

Scheme 47. Direct functionalization of isoxazole through the generation of 4-

Br
O O N isoxazolyl anion species 182.
XPhos Pd G 3 O O
O
O (10 mol %)
N N
ZnOPiv + N O
O THF, 50 °C, 16 h Several incorporation methods of fluorine into isoxazoles 185
178 have been reported. Tang et al.57 developed a decarboxylative
176 SO2 Me 13%
177
SO2 Me fluorination of isoxazole carboxylic acid 184 by using
i-Pr SelectfluorTM (Scheme 48).
PCy2
i
Pr i-Pr
H2 N Pd OSO 2Me Ph Me Ph Me
KF (4.0 equiv)
OH + Selectfluor N
N F
O DCE/H 2O (2:1) O
XPhos Pd G3
O 70 °C, 15 h
184 185
80%
Scheme 45. Pd-catalyzed Negishi coupling of isoxazole zinc pivalates 176.
Scheme 48. Decarboxylative fluorination of isoxazole carboxylic acids.
54
Sasai et al. developed a direct C–H arylation of various 3-
substituted and 3,4-disubstituted isoxazoles 179 (Scheme 46). The direct fluorination of isoxazoles at the C-4 position was
The use of 1,2-bis(diphenylphosphino)benzene (dppBz) enabled also demonstrated by Sato et al.58 3,5-Disubstituted isoxazoles
the introduction of various aryl iodides into the C-5 position of underwent fluorination with Selectfluor TM to afford the
the isoxazoles; however, the direct C–H arylation of 3- corresponding 3,5-disubstituted 4-fluoroisoxazolines 186 in
moderate yields (Scheme 49). The use of excess SelectfluorTM
gave 4,4,5-trifluoroisoxazoles 187.
Selectfluor 
N O N O N O
(1.0 equiv.)
R R1 R R1 R R1
sulfolane F
120 °C (oil bath), 1 h F F F
34 186 187

N O N O N O
Ph Ph
MeO OMe F3C CF 3
F F F

unsubstituted isoxazoles was not reported. 186a, 44% 186b, 32% 186c, 16%

NH2OH·HCl (3 equiv.) N O
O O
Selectfluor (1.0 equiv.) 6 examples
Scheme 46. Direct C–H arylation of isoxazoles 179 at the C-5 position. R R1
R R1 78-95%
sulfolane
F
150 °C (µW), 15 min 186
24

Scheme 49. Direct fluorination of isoxazoles 34 at the C-4 position.

12 Tetrahedron
Acknowledgment
Shen et al.59 developed a new electrophilic This research is partially supported by the Japan Society for the
difluoromethylthiolating reagent, N- Promotion of Science (JSPS, ID No. 17J02929).
diflouoromethylthiopthalimide 188, which was easily prepared in
four steps from readily available pthalimide and TMSCF2H.
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14 Tetrahedron

Highlights

► Recent synthesis approaches to functionalized

isoxazoles is reviewed.
► Synthesis of isoxazole framework is described.
► Direct fuctionalizations of isoxazoles are also
introduced.