TEMPO-Mediated Selective Synthesis of Isoxazolines, 5-Hydroxy-2-isoxazolines, and Isoxazoles via Aliphatic δ-C(sp3)-H Bond Oxidation of Oximes

Article abstract of DOI:10.1002/asia.202100572

Selective synthesis of three different bioactive heterocycles; isoxazolines, 5-hydroxy-2-isoxazolines and isoxazoles from the same starting material using TEMPO (2,2,6,6-Tetramethylpiperidin-1-oxyl) as a radical initiator is reported. Selectivity was achi

Full text of DOI:10.1002/asia.202100572

doi.org/10.1002/asia.202100572
Full Paper
TEMPO-Mediated Selective Synthesis of Isoxazolines, 5-Hydroxy-2-
isoxazolines, and Isoxazoles via Aliphatic δ-C(sp3)-H Bond
Oxidation of Oximes
Santanu Mondal+,[a, b] Sourabh Biswas+,[a] Krishna Gopal Ghosh,[a] and
Devarajulu Sureshkumar*[a]
Abstract: Selective synthesis of three different bioactive
heterocycles; isoxazolines, 5-hydroxy-2-isoxazolines and iso-
xazoles from the same starting material using TEMPO (2,2,6,6-
Tetramethylpiperidin-1-oxyl) as a radical initiator is reported.
Selectivity was achieved using different oxidants with TEMPO.
The reaction goes through a 1,5-HAT (hydrogen atom trans-
fer) process resulting in products with good yields. This
strategy offers a straightforward route to three different
heterocycles from oximes via radical-mediated C(sp3)-H
oxidation.
Introduction
Isoxazoles are also extensively used as 1,3-dicarbonyl equiv-
alents in natural product synthesis.[11] These heterocycles are
generally synthesized via [3+2] dipolar cycloaddition of nitrile
oxide and olefins (Figure 1B).[12] Although this strategy works
well in most of the cases, it has disadvantages such as (i) nitrile
oxide is prepared from unstable hydroxamoyl chlorides[13] or by
the hydrolysis of nitroalkanes,[14] usually under harsh conditions;
and (ii) poor-regioselectivity with unbiased olefins,[15] which
leads to difficulties in separating the two regio-isomers. Given
the relevance of isoxazoles and isoxazolines in organic and
medicinal chemistry and the limitations of the existing synthesis
method, it is highly desirable to find a new and efficient
complementary method. In this context, radical-mediated direct
functionalization methods can be valuable as it offers broad
substrate scope, easy separation of regio-isomers, and mild
reaction conditions.
Selective and direct functionalization of non-activated sp3
carbon atoms is a longstanding challenge in organic synthesis.[1]
Reactivity of aliphatic CÀ H bonds decreases with increasing
distance from the closest reactive functional group (e.g.,
carbonyl group), and hence regioselective functionalization of
remote aliphatic CÀ H bonds is very difficult.[2] In this context,
radical-mediated functionalization is a method of choice in
recent years as it has a significant advantage over other 2eÀ
processes (e.g., rearrangement, fragmentation etc).[3] Over the
past years, radical-mediated functionalization of C(sp3)-H bonds
via 1,5-hydrogen atom transfer (HAT) has been well studied.[4]
Direct functionalization is one of the most atom and step-
economical, especially for the synthesis of complex moiety from
a simple precursor.[5]
Isoxazoles and isoxazolines are the five-member nitrogen-
containing heterocycles that contain two electronegative atoms
(N and O) in 1, 2 relationships. Thus, these scaffolds could take
part in hydrogen bonds, donor-acceptor interactions with
various enzymes and receptors.[6] Currently, various life-saving
drugs contain isoxazoles and isoxazolines moieties (Figure 1A)[7]
and 5-hydroxy-2-isoxazolines have been utilized as a versatile
synthon possibly because it can be easily transformed into
various functional groups like isoxazoles, β-enaminones, 1,3-
diketones, γ-amino alcohols, and N-aryl-β-lactams, etc.[8–10]
Chiba and co-workers have developed a radical-mediated
protocol for the synthesis of isoxazolines.[16] This protocol was
limited to only the synthesis of di-substituted isoxazolines
(Figure 2). Later, an improved system was developed for the
synthesis of isoxazolines using selectfluor/Bu4NI by Liu and co-
workers.[17] Other than these, there is no report on the divergent
synthesis of isoxazoles and isoxazolines from oximes via the 1,5-
HAT process.
Here, we have developed conditions based on a different
strategy to synthesize three different heterocycles using mild
conditions and cheap inorganic oxidants. This methodology
also covers a broad range of substrates scope with moderate to
excellent yields with good selectivity. Further, our method can
also be elegantly controlled with the help of oxidants.
[a] S. Mondal,+ S. Biswas,+ K. G. Ghosh, Dr. D. Sureshkumar
Department of Chemical Sciences
Indian Institute of Science Education and Research (IISER) Kolkata
Mohanpur, West Bengal 741246 (India)
E-mail: suresh@iiserkol.ac.in
Homepage: https://www.iiserkol.ac.in/~suresh/
Results and Discussion
[b] S. Mondal+
Okinawa Institute of Science and Technology Graduate University (OIST)
Okinawa (Japan)
[+] These authors contributed equally.
As an initial approach to synthesize isoxazoline 2a, we used
TEMPO as a radical initiator and K2S2O8 as the oxidant in the
presence of oxime 1a as a model substrate in acetonitrile
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/asia.202100572
This manuscript is part of a special collection celebrating the 15th Anni-
versary of IISER Inception.
°
(MeCN) solvent at 50 C. We observed that 3.0 equiv. of K2S2O8
and 0.4 equiv. of TEMPO could produce a mixture of isoxazoline
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Figure 1. A) Examples of bioactive molecules containing isoxazole and isoxazoline. B) [3+2] Dipolar cycloaddition of nitrile oxides and olefins.
2a and isoxazole 3a in 4.0 mL of MeCN (Table 1, entry 4). We
first investigated the effect of the solvent amount in the
product formation (Table 1, entry 1–8). We obtained the
maximum yield of isoxazoline when we used 6.0 mL of MeCN
(75% isoxazoline 2a; 15% isoxazole 3a) (Table 1, entry 6).
Different solvents like DMF, DCE, and 1,4-Dioxane were also
screened, but the results were not satisfactory (see Supporting
Information, SI). Interestingly, with 30 equiv. of water, the
formation of isoxazoline 2a could be enhanced to 83%
(entry 13). Water was found to be critical to increase the yield,
which might be due to the increased solubility of K2S2O8.
Therefore, the optimized reaction conditions for the isoxazo-
lines (2a) synthesis were oxime 1a (1.0 equiv, 0.2 mmol),
TEMPO (0.4 equiv), K2S2O8 (3.0 equiv) and H2O (30 equiv) in
°
MeCN (6.0 mL) at 50 C for 30 h (Table 1, entry 13).
We noted that decreasing the solvent volume increased the
formation of isoxazole 3a (Table 1, entry 1–3), although the
overall yield was low. We hypothesized that by varying different
oxidants under low solvent volume, in situ, we could oxidize
isoxazoline 2a to isoxazole 3a. Thus, it would give us a protocol
for a one-pot synthesis of isoxazole 3a from oxime 1a. To test
this, we started with 2.0 mL of MeCN and observed an
improved yield of 3a up to 55% using K2S2O8 (5.0 equiv)
(Table 1, entry 15). Different oxidants like NaIO4 and oxone
(KHSO5 ·0.5KHSO4 ·0.5 K2SO4) were screened, but the yield of 3a
did not improve any further. However, when a combination of
oxone (2.0 equiv) and KI (0.1 equiv) was used, the conversion
was increased to 99% (Table 1, entry 18) with the product ratio
of 41:58 (2a:3a). We got the best yield of isoxazole (88%)
using 3.0 equiv. of oxone and 0.1 equiv. of KI (Table 1, entry 20).
This result is in line with hypoiodite mediated oxidative reaction
Figure 2. Previous literature report and this work.
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Table 1. Optimization conditions for the synthesis of 2a, 3a, 4a from oxime 1a.[a]
Entry
TEMPO
[equiv]
Oxidant
[equiv]
Solvent
[mL]
Additive
[equiv]
Time
[h]
Yield[b]
[%]
Yield[b]
[%]
Yield[b]
[%]
2a
3a
4a
1
2
3
4
5
6
7
8
12
13
14
15
16
17
18
19
20
21
22
23
24
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
1.5
1.5
1.5
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (5)
NaIO4 (3)
Oxone (1.5)
Oxone (2)
Oxone (2.5)
Oxone (3)
PhI(OAc)2 (1)
PhI(OAc)2 (0.5)
PhI(OAc)2 (1)
PhI(OAc)2 (1.5)
1
2
3
4
5
6
7
8
6
6
6
2
2
2
2
2
2
6
6
6
6
–
–
–
–
–
–
–
–
30
30
30
30
30
30
30
30
30
30
30
48
48
48
48
48
48
24
24
24
24
30
25
34
43
65
75
70
41
67
83 (81)[c]
71
25
60
34
41
19
5
43
54
52
50
22
15
7
27
17
8
17
55
19
5
58
78
88 (84)[c]
1
-
-
–
–
–
–
–
–
–
–
–
–
–
–
–
–
H2O (60)
H2O (30)
H2O (20)
–
–
–
KI (0.1)
KI (0.1)
KI (0.1)
–
39
50
3
1
2
2
–
–
–
5
0
2
73 (70)[c]
38
°
°
[a] Reaction conditions: 1a (0.2 mmol), TEMPO (0.4–1.5 equiv), oxidant (1.0–5.0 equiv) in MeCN (1.0–6.0 mL) at 25 C or 50 C for 24 h–48 h. Entry (1–14), (15–
20), and (21–24) reactions were carried out for 30 h, 48 h and 24 h respectively. [b] Yields were calculated by 1H NMR using 1,1,2,2 tetrachloroethane as an
internal standard. [c] Isolated yields are given in parenthesis.
was already reported using the oxone-KI system, where the
generation of the activated iodine species was crucial for the
transformation.[18]
phenyl ring (1c, 1f, 1g), when reacted with the optimized
conditions, also gave the corresponding isoxazoline (2c, 2f, 2g)
in good yields. However, low yields and selectivity were found
in the case of oxime containing p-methoxy (1d) and o-fluoro
(1e) substitution. Particularly, when the substitution was p-
methoxy, the reaction produced significantly more isoxazole 3d
than isoxazoline 2d. This could be attributed to in situ oxidation
of 2d to 3d because of the high reactivity of the phenyl ring
being substituted with an electron donating group (-OMe).
When the phenyl ring was substituted with thiophene moiety,
corresponding isoxazoline 2n was isolated in very less yield.
The reaction of oxime 1o was very sluggish. Oxime 1p, 1q, and
1r when reacted under the standard conditions, did not yield
the expected product. These results can be correlated to the
stability of the radical intermediate (benzylic radicals are more
stable than alkyl radicals), which is important for the product
formations. Various substituted oximes containing tertiary
methine moieties (1s–1w) produced corresponding isoxazo-
lines (2s–2w) in excellent yields (single isomer).
A new product 5-hydroxy-2-isoxazoline 4a was obtained
when PhI(OAc)2 was used as an oxidant. The formation of 4a
was found to be very selective in the presence of PhI(OAc)2. Our
first trial reaction produced 39% of 4a with the combination of
0.4 equiv. of TEMPO and 1.0 equiv. of PhI(OAc)2 at room
temperature under N2 atmosphere (Table 1, entry 21). We found
the best yield of 4a up to 73% using 1.5 equiv. of TEMPO and
1.0 equiv. of PhI(OAc)2 (Table 1, entry 23).
With the optimized experimental conditions for all the three
heterocycles 2a, 3a, and 4a, we decided to define the substrate
scope of isoxazoline 2a and the limitations of the reaction. The
results are summarized in Scheme 1. Oxime 1 bearing both
electron-donating and electron-withdrawing substitutions on
the phenyl ring produced moderate to good yields. Various
substitutions at the R1 of oximes like p-methoxy, p-fluoro, p-
chloro, and p-bromo (1h, 1k, 1l, 1m) produced corresponding
isoxazolines (2h, 2k, 2l, 2m) with a yield ranging from 61% to
73%. Oxime containing naphthyl ring (1j) and 3,4-(meth-
ylenedioxy)benzene ring (1i) afforded desired products in 70%
and 63% respectively. Oximes with substitution at the R2 of the
Optimized conditions for the isoxazoles synthesis also work
well on different derivatives of oximes (Scheme 2). The reaction
produced the best yield when the R2 side of the oximes was
substituted with electron-donating groups. Oximes 1a–1d gave
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Scheme 2. Scope of the Synthesis of Isoxazole 3 from Oxime 1: [Reaction
conditions: 1 (0.2 mmol), TEMPO (0.4 eq), oxone (3.0 equiv), KI (0.1 eq) in
°
MeCN (2.0 mL) at 50 C for 48 h. Ratios (3:2) were calculated from the
isolated yields. [a] 1H NMR yield was recorded].
(1k–1m) all reacted smoothly to give moderate yields of 3k–
3m. Alkyl oximes (1o, 1p), pyrrole and pyridyl substituted
oximes (1q, 1r), when reacted with the standard conditions,
failed to yield the expected products.
Scheme 1. Scope of the Synthesis of Isoxazoline 2 from Oxime 1: [Reaction
conditions: 1 (0.2 mmol), TEMPO (0.4 eq), K2S2O8 (3.0 eq), water (30 eq) in
°
MeCN (6.0 mL) at 50 C for 30 h. Ratios (2:3) were calculated from the
The reaction conditions developed here work well with
isolated yields. [a] 1H NMR yield was recorded].
various oximes
1 to produce 5-hydroxy-2-isoxazoline 4
(Scheme 3). Different substituted oximes (R1 and R2) were well
tolerated and gave high yields with good selectivity. Various 5-
hydroxy-2-isoxazoline bearing substitutions at the R2 side like p-
ethyl (4c), p-methoxy (4d), o-fluoro (4e), p-fluoro (4f) and p-
chloro (4g) were obtained in high yields and selectivity. Oximes
bearing substitutions at the R1 position of the phenyl ring also
proceeded efficiently to furnish the corresponding products
4h–4m.
Thiophene derived hydroxy isoxazoline 4n was obtained in
13% yield with the standard reaction conditions. The reaction
was uncontrolled in case of oxime 1o and the product
formation was <9% (1H-NMR yield). No detectable product
formation was observed with oximes 1p, 1q, and 1r. In general,
corresponding isoxazoles 3a–3d in the range of 76–84% yields.
The reaction furnished low yields and selectivity when electron-
withdrawing groups were present at the R2 position.
Fluorinated isoxazoles 3e and 3f were obtained in 42% and
40% yields, respectively. It is worth noting that the substitution
effect is less prominent on product formation when the
substitutions are present on the R1 side of the phenyl ring than
the R2 side. Oxime containing naphthyl (1j) and 3,4-(meth-
ylenedioxy)benzene (1i) group afforded the products 3j and 3i
in 73% and 74% yields respectively with good selectivity.
Oximes containing (at R1 side) fluorine, chlorine, and bromine
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Table 2. Background study: Oxidation of isoxazoline to isoxazole.[a,b]
Entry
Deviation from the standard condition[a]
Yield[b]
[%]
1
2
3
4
–
84
4
60
<1
oxone (1.0 equiv)
without KI
TEMPO (0.4 equiv)
[a] Reaction conditions: 1a (0.2 mmol), TEMPO (0.4 eq), oxone (1.0 eq) and
1
°
KI (0.1 eq) in MeCN (2.0 mL) at 50 C for 48 h. [b] H NMR yields were
calculated using equivalents amount of 1,1,2,2 tetrachloroethane as an
internal standard.
showed an efficient oxidation strategy to convert isoxazoline to
isoxazole using nitric oxide (NO).[19]
A plausible mechanism is proposed for the divergent
synthesis of isoxazoline 2a and isoxazole 3a from oxime 1a, as
shown in Scheme 4. In the case of isoxazoline synthesis, in the
first step, TEMPO generates an iminoxyl radical A in the
presence of K2S2O8 from oxime 1a. Radical A undergoes a 1,5-
Scheme 3. Scope of the reaction: Synthesis of 5-hydroxy-2-isoxazoline 4
from oxime 1: [Reaction conditions: 1 (0.2 mmol), TEMPO (1.5 eq), PhI(OAc)2
(1.0 eq), in MeCN (6.0 mL) at room temperature for 24 h under N2
atmosphere. Ratios (4:2) were calculated from the isolated yields. [a] 1H
NMR yields].
the conditions developed for the synthesis of 4 were less
influenced by different substituents, unlike in the radical-
mediated synthesis of isoxazole 3 and isoxazoline 2.
Background experiments were carried out to justify our
hypothesis for the in situ oxidation of isoxazoline 2 to isoxa-
zole 3. Isoxazoline 2a was taken as a starting compound for the
experiment. Isoxazole 3a was obtained in 84% when 2a was
subjected to the conditions: TEMPO (0.4 equiv), oxone
°
(1.0 equiv), KI (0.1 equiv) in 2.0 mL of MeCN at 50 C. Product 3a
was found in much lower yield (4%) when the reaction was
carried out using only oxone (Table 2, entry 2). When the same
reaction was performed without KI, yield of 3a was 60%
(Table 2, entry 3). Isoxazole 3a was formed <1% in the
presence of only 0.4 equivalent of TEMPO (Table 2, entry 4).
These results suggest that oxone alone cannot promote the
oxidation of 2a to 3a. It is also highlighting the essential role of
TEMPO and KI.
The oxidation reaction may follow
a single electron
oxidation pathway similar to the report of Wu et al., where they
Scheme 4. Plausible mechanism for the divergent synthesis of 2a and 3a
from oxime 1a.
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hydrogen atom transfer (HAT) reaction to give the correspond-
ing carbon center radical B, which further reacts with TEMPO
and after elimination produces D. Finally, D takes part in
cyclization to give isoxazoline 2a.
In the case of isoxazole synthesis, I+ might be involved in
the key oxidation step.[18] At the initial stage of the reaction,
TEMPO generates an iminoxyl radical A’ with the help of oxone/
KI (Scheme 4). Intermediate A’ would be likely to follow a similar
route (A’ to D’) to produce isoxazoline 2a. Next, hypoiodite
mediated oxidation occurs to give isoxazole 3a (Scheme 4 and
Table 2). Efficient in situ oxidation of 2a to 3a is hypothesized
as the key step in this reaction.
To gain more insight into the reaction mechanism, we have
carried out reactions with acetyl protected oximes. When acetyl
protected oxime 5 was subjected to the standard reaction
condition for the synthesis of 2, the reaction produces a mixture
of products, oximes 1a and isoxazolines 2a in low yields
(Scheme 5). The reaction did not proceed when oxime 6 was
treated with reaction condition used to make 2. No reactions
occurred when the acetyl protected oximes 5 and 6 were
treated with reaction conditions used to make 3 and 4. When
oxime 7 was subjected to the standard reaction conditions of
isoxazole synthesis, it yielded dimeric-isoxazole derivative 8 by
radical-mediated ring-opening of cyclopropane (Scheme 5).
These results clearly indicate the importance of O-radical
formation in the reaction (intermediate A or A’, Scheme 4) and
support the involvement of 1,5 HAT step. Also, these results
ruled out the possibility of direct benzylic radical formation (B
or B’, Scheme 4) from the oxime 1a.
Scheme 5. Mechanism study: Evidence of radical based pathway [Reaction
conditions: 0.2 mmol of 5, 6 is used for the reactions. Yields were calculated
from the crude reaction mixture, using equivalent amount of tetrachloro-
ethane].
Our result shows that 1.5 equivalents of TEMPO is necessary
to get the best yield that may be correlated to the source of
extra oxygen, which is crucial for the formation of 5-hydroxy-2-
isoxazoline 4. A plausible mechanistic route is proposed, as
shown in Scheme 6. In the presence of TEMPO (2,2,6,6-tetra-
methylpiperidin-1-oxyl), oxime 1 produced an oxygen-centered
radical (I), which subsequently undergoes 1,5-HAT, oxidation
reaction and produces intermediate (III). This reacts with
TEMPO-H to form intermediate (IV). Then, the intermediate (IV)
may react with PhI(OAc)2 to give intermediate (V) that takes
part in an elimination reaction and forms intermediate (VI),
which, after an intramolecular cyclization reaction, provides the
final product 4.[20]
Conclusion
In summary, an efficient synthesis protocol for three hetero-
cycles, 2-isoxazolines, 5-hydroxy-2-isoxazolines, and isoxazoles
have been developed using TEMPO and a combination of
oxidants from the same oxime. Inexpensive inorganic peroxides
K2S2O8 and oxone (KHSO5 ·0.5 KHSO4 ·0.5 K2SO4) have been used
for the synthesis of 2-isoxazolines and isoxazoles. We also report
an efficient synthesis protocol for 5-hydroxy-2-isoxazolines, a
versatile synthon to obtain various value-added functional
moieties such as isoxazole and γ-amino alcohols. Finally, the
synthesis of isoxazole is shown using in situ radical-mediated
oxidation of isoxazoline.
Scheme 6. Possible mechanistic route for the synthesis of 5-hydroxy-2-
isoxazoline 4 from oxime 1.
Experimental Section
General Information
Dry solvents were used for the reaction development. Reagents
were purchased from commercial suppliers (Alfa Aesar, Spectro-
chem, Sigma-Aldrich, and TCI). Reactions were performed in a dried
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glassware with a magnetic stirring bar placed inside. Merck silica
gel (230–400 mesh) was used for the flash column chromatography.
Ethyl acetate and hexane mixture was used as an eluent system to
purify all the compounds. Buchi rotary evaporator was used to
concentrate the organic solutions. The yields were calculated from
General Procedure for the Synthesis of
5-Hydroxy-2-Isoxazolines 4 from Oximes 1
Oxime 1 (0.2 mmol, 1.0 equiv), TEMPO (0.3 mmol, 1.5 equiv), and
PhI(OAc)2 (0.2 mmol, 1.0 equiv) in MeCN (6.0 mL) were added to an
oven-dried glass tube equipped with a magnetic stir bar. The
reaction was continued for 24 h under N2 atmosphere. Water was
added, and the mixture was extracted with ethyl acetate (3 times).
The combined organic layer was dried over sodium sulphate. Rotary
evaporator was used to remove the solvent. The crude product was
then purified by flash column chromatography using silica gel
(mesh 230 400). Hexane and ethyl acetate (93:7 to 89:11) as
eluents were used to afford the corresponding 5-hydroxy-2-isoxazo-
line derivatives.
1
the products obtained after column purification. H and 13C NMR
spectra were recorded on a 400 MHz Jeol and 500 MHz Bruker.
Proton chemical shifts are reported in ppm downfield from relative
to the residual 1H signal of CDCl3 (δ 7.26ppm) and DMSO-d6
(δ 2.50ppm). Carbon chemical shifts were internally referenced to
the deuterated solvent signals in CDCl3 (δ 77.16ppm) and in DMSO-
d6 (δ 39.52ppm). Coupling constants (J) are measured in hertz (Hz).
General Procedure for the Synthesis of Oximes 1
All oximes were prepared according to the reported literature
procedure.[21] To a solution of ketone (1.0 equiv) in EtOH (0.5 M) was
added hydroxylamine hydrochloride (1.5 equiv) and NaOAc
(2.0 equiv). The reaction mixture was then stirred at room temper-
General Procedure for the Synthesis of Acetyl Protected
Oximes 5 and 6
Oxime (1.0 equiv) and acetyl chloride (1.5 equiv) were dissolved in
dichloromethane, and the mixture was cool with an ice-bath.
Triethylamine (1.5 equiv) was added dropwise. The reaction mixture
was brought to room temperature and stirring was continued for
4 hours. Water was added to the reaction mixture, and the organic
phase was separated. The organic phase was washed with
saturated NH4Cl, aqueous Na2CO3 solution, and brine. The organic
layer was dried over sodium sulphate and evaporated in rotary
evaporator. The residue was purified by column chromatography
using hexane and ethyl acetate (93:7) as eluent.
°
ature or heated at 60 C until the ketone was consumed as
monitored by TLC (TLC Silica gel 60 F254). The solvent was
evaporated, and the residue was diluted with water and ethyl
acetate. The aqueous layer was extracted with ethyl acetate. The
combined organic layers were washed with 1.0 N aqueous HCl and
brine. Organic layer was dried over Na2SO4 and concentrated in a
rotary evaporator. Purification of the crude product by flash column
chromatography using hexane/ethyl acetate as eluent afforded the
corresponding oxime.
General Procedure for the Synthesis of Isoxazolines 2 from
Oximes 1
Acknowledgements
Oxime 1 (0.2 mmol, 1.0 equiv), TEMPO (0.08 mmol, 0.4 equiv),
K2S2O8 (0.6 mmol, 3.0 equiv), and H2O (6.0 mmol, 30 equiv) in MeCN
(6.0 mL) were added to an oven-dried glass tube equipped with a
magnetic stir bar. Next, the tube was placed in a pre-heated oil-
D. S. thanks the IISER Kolkata for startup Grant, SERB for Early
Career Research Award (ECRA) and DST-SERB for Ramanujan
Fellowship. S. M., S. B., and K. G. G. thanks IISER-K, IISER-K, and
DST their PhD fellowship.
°
bath at 50 C. The mixture was stirred at the same temperature for
30 h. Water was added, and the mixture was extracted with ethyl
acetate (3 times). The combined organic layer was dried over
Na2SO4. Solvent was removed in a rotary evaporator. The crude
product was then purified by flash column chromatography on
silica gel (mesh 230 400) using hexane and ethyl acetate (97:3 to
94:6) as eluents to afford the corresponding isoxazoline derivatives.
Conflict of Interest
The authors declare no conflict of interest.
General Procedure for the Synthesis of Isoxazoles 3 from
Oximes 1
Keywords: isoxazolines · isoxazoles · heterocycles · hydrogen
atom transfer (HAT) · divergent synthesis
Oxime 1 (0.2 mmol, 1.0 equiv), TEMPO (0.08 mmol, 0.4 equiv),
oxone (0.6 mmol, 3.0 equiv), and KI (0.02 mmol, 0.1 equiv) in MeCN
(2.0 mL) were added to an oven-dried glass tube equipped with
a magnetic stir bar. The tube was placed in a pre-heated oil-bath at
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Manuscript received: May 27, 2021
Revised manuscript received: June 20, 2021
Accepted manuscript online: June 30, 2021
Version of record online: ■■■, ■■■■
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FULL PAPER
S. Mondal, S. Biswas, K. G. Ghosh,
Dr. D. Sureshkumar*
1 – 9
TEMPO-Mediated Selective
Synthesis of Isoxazolines, 5-
Hydroxy-2-isoxazolines, and Iso-
xazoles via Aliphatic δ-C(sp3)-H
Bond Oxidation of Oximes
Three heterocycles from one starting
material: A divergent method for the
synthesis of isoxazolines, isoxazoles,
and 5-hydroxy-2-isoxazolines from
oximes is developed using TEMPO as
a radical initiator. Oxidants control the
selectivity of the product formations.