Catalytic Enantioselective Synthesis of 3,4,5-Trisubstituted Isoxazoline N-Oxides and Regioselective Synthesis of 3,4,5-Trisubstituted Isoxazoles

Article abstract of DOI:10.1002/ejoc.201801693

An efficient catalytic asymmetric synthesis of 3,4,5-trisubstituted isoxazoline N-oxides and regioselective synthesis of 3,4,5-trisubstituted isoxazoles has been described. α-Nitrocinnamates and α-nitrobenzophenones were utilized as Michael acceptors resp

Full text of DOI:10.1002/ejoc.201801693

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Accepted Article
Title: Catalytic Enantioselective Synthesis of 3,4,5-Trisubstituted
Isoxazoline N-oxides and Regioselective Synthesis of 3,4,5-
Trisubstituted Isoxazoles
Authors: Subas Chandra Sahoo and Subhas Chandra Pan
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801693
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Catalytic Enantioselective Synthesis of 3,4,5-Trisubstituted
Isoxazoline N-oxides and Regioselective Synthesis of 3,4,5-
Trisubstituted Isoxazoles
Subas Chandra Sahoo and Subhas Chandra Pan*[a]
Dedication ((optional))
Abstract: An efficient catalytic asymmetric synthesis of 3,4,5-
trisubstituted isoxazoline N-oxides and regioselective synthesis of
inhibition of casein kinase. [13] These bioactivities have prompted
the development for the synthesis of a variety of trisubstituted
isoxazoles.[14] Although the reported methods have been
demonstrated effective in the preparation of isoxazoline and
isoxazoline N-oxides with specific structures, there is still
requirement for the exploration of new and efficient synthetic
methods for structurally diverse isoxazoline N-oxides and
isoxazolines. Here in, we report a direct synthesis of chiral
isoxazoline N-oxides from ethyl α-nitrocinnamates and ethyl
nitroacetate and also regioselective synthesis of isoxazolines
from α-nitrochalcones and nitroketones.
3,4,5-trisubstituted
isoxazoles
has
been
described.
α-
Nitrocinnamates and α-nitrobenzophenones were utilized as Michael
acceptors respectively. Hydroquinine derived thiourea in combination
with cesium carbonate was effective for the synthesis of isoxazoline
N-oxides whereas stoichiometric di-isopropylethylamine (DIPEA) was
the best choice for isoxazole synthesis. In both cases a range of aryl
and heteroaromatic groups was tolerated.
Introduction
Isoxazoline N-oxides, important five-membered heterocycles, are
familiar precursors for the synthesis of highly functionalized γ-
hydroxy-α-amino acids or γ-amino-α-hydroxy acids,[1,2] natural
products,[1c,3] and biologically active compounds.[4] Owing to their
versatile use in organic synthesis,
a range of synthetic
approaches for the preparation of isoxazoline N-oxides have been
documented.[3,5] In the past, the synthesis of chiral isoxazoline N-
oxides relied on the use of optically pure starting materials[5] and
on stoichiometric quantities of chiral reagents[6]. Recently a few
catalytic asymmetric strategies have been reported in the
literature (Scheme 1).[7] Jørgensen and co-workers reported a
one pot synthesis of functionalized chiral isoxazoline N-oxides
through α-bromination, Henry reaction and cyclization
sequence.[7a] Zhong and co-workers reported secondary amine
catalysed [4+1] annulation between α-iodo aldehydes and (E/Z)-
nitrocinnamates.[7b] Maruoka group developed a phase transfer
catalysed conjugate addition of bromomalonates to nitroolefins
followed by cyclization for the synthesis of isoxazoline N-
oxides.[7c-d] Zhu group utilized quinine as a catalyst for the
cyclization reaction between Morita Baylis Hillman adducts and
chloro-1,3-diketones.[7e] However, halogen free synthesis of chiral
isoxazoline N-oxides was not reported.
Similarly, isoxazoles are often found in natural products and
biologically active compounds as well as used as building blocks
in organic synthesis.[8,9] In particular 3,4,5-trisubstituted
oxazoles[10] have drawn attention in view of their biological
antagonism,[11] antibacterial and antifugal activities[12] and
Scheme 1: Catalytic asymmetric synthesis of isoxazoline N-oxides
Results and Discussion
We began our investigation by reacting α-nitrocinnamate 1a and
ethyl nitroacetate 2a with Takemoto catalyst (I) in the presence of
sodium carbonate in chloroform and little amount of water at room
temperature (Table 1). Delightfully, after stirring for 7 days, the
desired isoxazoline N-oxide 3a was formed in 30% yield and
>20:1 diastereomeric ratio but the enantioselectivity was poor
(Table 1, entry 1). To improve the enantioselectivity, hydroquinine
derived thiourea catalyst II was employed but only little
enhancement was observed (Table 1, entry 2). Squaramide
[a]
S. C. Sahoo and Prof. Dr. S. C. Pan
Department of Chemistry
Indian Institute of Technology Guwahati
Assam, 781039, India
E-mail: span@iitg.ernet.in
Webpage: www.iitg.ac.in/span
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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catalyst III was also found to be not efficient for this reaction. Then
we prepared hydroquinine derived urea catalyst IV and better
yield as well as enantioselectivity (82:18 er) was detected (Table
1, entry 4). Cinchonidine derived urea catalyst V was also
screened and provided the product 3a in lesser yield and
enantioselectivity. Thus catalyst IV was used for further
optimization. Consequently we turned our attention on the
screening of different bases and it proved to be fruitful. Though
potassium carbonate could not improve the enantioselectivity, a
higher enantioselectivity (86:14 er) was obtained with cesium
carbonate (Table 1, entries 6-7). Then we decided to change the
equivalents of cesium carbonate in the reaction. Infact the best
result (93:7 er) was achieved with 4 equivalents of cesium
carbonate (Table 1, entries 8-9). Other solvents were also
screened (see supporting information for details) but inferior
results were obtained.
gel column chromatography.[c] Determined by chiral HPLC. [d] Two equivalents
of Cs2CO3. [e] Four equivalents of Cs2CO3.
After the optimized conditions got established, the scope of ethyl
α-nitrocinnamates in the reaction was investigated. As displayed
in Table 2, a wide range of aryl group containing nitrocinnamates
could be employed in the reaction and moderate to good results
were achieved. Also, pleasingly, in all of the cases, only a single
diastereomer formation was observed. Initially, different ortho-
substituted aryl groups were tested and delightfully good results
were obtained. For example, o-tolyl containing nitrocinnamate 1b
delivered product 3b in 65% yield with 95:5 er. Nitrocinnamate 2c
having 2-anisyl substituent also participated in the reaction with
acceptable yield and slight lower enantioselectivity was detected.
Halo substitutions were also tolerated and products 3d and 3e
were isolated in good yields. It is interesting that the
enantioselectivity of 3e was higher than 3d. Then m-substituted
nitrocinnamates 1f and 1g were screened in the reactions and
moderate enantioselectivities were achieved for products 3f and
3g. Our methodology was also found to be suitable for o-
substiuted nitrocinnamates and good results were observed. In
particular, product 3j having 4-fluoro substituent was isolated in
78% yield with 90:10 er. 1-Naphthyl substituted nitrocinnamate 1l
also took part in the reaction to deliver product 3l in moderate
enantioselectivty. Finally furyl substituted nitrocinnamate 1m was
employed in the reaction and similar result was observed.
Table 1. Catalyst screening and optimization of the reaction conditions for the
synthesis of isoxazoline N-oxide 3a
Table 2. Scope of nitrocinnamates in the synthesis of isoxazoline N-oxides
Entry[a]
R
3
3a
3b
3c
3d
3e
3f
Yield[b](%) dr[c]
er[d]
1
Ph
70
65
70
80
78
72
75
78
75
78
74
78
35
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
93:7
2
2-MeC6H4
2-OMeC6H4
2-FC6H4
2-ClC6H4
3-MeC6H4
3-ClC6H4
4-MeC6H4
4-OMeC6H4
4-FC6H4
4-ClC6H4
1-naphthyl
2-furyl
95:5
Entry[a]
Catalyst
I
Base
Yield[b]
30
er[c]
3
86:14
85:15
92:8
1
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
45:55
57:43
55:45
82:18
73:27
73:27
86:14
89:11
93:7
4
II
40
5
3
III
IV
V
42
6
86:14
84:16
75:25
80:20
90:10
82:18
77:23
78:22
4
72
7
3g
3h
3i
5
65
8
6
IV
IV
IV
IV
72
9
7
Cs2CO3
Cs2CO3
Cs2CO3
78
10
11
12
13
3j
8[d]
9[e]
75
3k
3l
70
[a] Reaction condition: Unless otherwise mentioned, 0.05 mmol of 1a and 0.05
mmol of 2 with 1 eq. base in 0.5 mL chloroform and 100 μL water using 10 mol%
catalyst and a single diastereomer was detected. [b] Isolated yield after silica
3m
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[a] Reaction conditions: 0.1 mmol of 1 and 0.1 mmol of 2 with 4 eq. Cs2CO3 in 1
mL chloroform and 200 μL water using 10 mol% catalyst IV. [b] Isolated yield
after silica gel column chromatography. [c] Determined by 1H NMR. [d]
Determined by chiral HPLC.
methoxy and 4-chloro substituents respectively, were obtained
with 5.6:1 and 5.1:1 regioisomeric ratios. Also, high
regioselectivity and acceptable yield was observed for product 6k
having 4-nitroaryl group. The regioselectivity got enhanced when
meta-substituted enone 4l was employed in the reaction. Our
methodology also worked with ortho-substituted enone 4m albeit
slight lower yield was observed for product 6m. A heteroaromatic
furyl group was also screend and the regioisomeric product 6n
was obtained as 4.6:1 mixture.
Then we screened organic base mediated reaction between
α-nitrobenzophenone 4a and nitroketone 5a and interestingly
using DBU as base, an isoxazole product 6a was isolated in 3:1
ratio along with the regioisomer 6a' (Table 3, entry 1).[15] The yield
as well as regioselectivity got improved with di-
isopropylethylamine (Table 3, entry 2). Then we turned our
attention on the solvent optimization. Interestingly, the yield got
decreased in toluene and also DMSO was not at all a good
solvent only providing 5% yield (Table 3, entries 3-4). Gratifyingly
a decent yield of 72% with a high regioselectivity was achieved in
acetonitrile (Table 3, entry 5).
Table 4. Scope of enones in the synthesis of isoxazoles [a],[b]
Table 3. Optimization of the reaction conditions for the synthesis of isoxazole
Entry[a] base
solvent time (h) Yield[b](%) 6a/6a'[c]
DBU
CHCl3
CHCl3
toluene
DMSO
24
36
36
36
36
68
71
55
5
3:1
3.5:1
2:1
-
1
2
3
4
5
DIPEA
DIPEA
DIPEA
[a] Reaction conditions: 0.1 mmol of 4 with 0.1 mmol of 5a in 1 ml CH3CN.
[b]Yields correspond to isolated yields after silica gel column chromatography
and regioselectivity was determined by 1H NMR.
DIPEA CH3CN
72
5:1
The generality of the reaction was further established by by
preparing isoxazoles with same ketofunctionalities (Table 5).
Thus the reaction of enone 1a with phenyl nitroketone 2b provided
the product 6o in 66% yield. Similarly other products 6p-6r were
isolated in good yields. In these cases, the cyclization happened
through a symmetrical intermediate.
[a] Reaction conditions: 0.05 mmol of 4a and 0.05 mmol of 5a in 0.5 mL solvent
using 2 eq. base at room temperature. [b]Isolated yield after silica gel column
chromatography. [c]Determined by 1H NMR.
After the best reaction conditions got established, the scope
and generality of the reaction 6 was ventured. Initially the keto-
functionality of α-nitrobenzophenone was varied and the results
are shown in Table 4. At the beginning, different para-
substitutions were tested and the products 6b-6d were obtained
in good yields and high to excellent regioselectivities. In particular,
product 6d having 4-chloro substitution was isolated as single
regioisomer in 80% yield. Then benzophenone 4e having 2,4-
dimethylphenyl group was employed and delightfully here also the
product 6e was attained as a single regioisomer. Smooth
conversion was also seen with thiphenyl enone 4f but in this case
the opposite regioisomer 6f' was formed as major product
because of more electron density of thiophene ring. Moreover an
alphatic enone 4g was also tolerated in the reaction, albeit slight
lower yield was observed. Then we turned our attention to check
different groups of the olefin functionality in enone 4 (Table 4).
Thus enones 4h-4k having electron donating and withdrawing
group at para-position were engaged in the reaction. Delightfully,
the products 6h-6k were isolated in acceptable yields and good
regioisomeric ratios. For example, products 6i and 6j having 4-
Table 5. Synthesis of isoxazoles with same keto functionalities [a],[b]
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[a] Reaction conditions: 0.1 mmol of 4 with 0.1 mmol of 5 in 1 ml CH3CN. [b]
Yields correspond to isolated yields after silica gel column chromatography.
Plausible mechanism has been shown in Scheme 2 to
explain the formation of products 3a and 6a. Initially ethyl α-
and regioselective synthesis of 3,4,5-trisubstituted isoxazoles.
Easily available starting materials α-nitrocinnamates, α-
nitrobenzophenones, nitroacetate and α- nitroketones were
employed in this method. The products 3,4,5-trisubstituted
isoxazoline N-oxides and isoxazoles could be useful in the
development of new pharmaceuticals.
nitrocinnamate
base to generate active nucleophile
α-nitrocinnamate 2a to provide . Intramolecular substitution
reaction in the resonance form with nitro as the leaving
2
gets deprotonated either by catalyst or
A
which then reacts with
B
Experimental procedures
C
group delivers product 3a. Similarly, for the formation of
isoxazole 6a, nitroketone 5a first gets deprotonated by
General procedure for the synthesis of Isoxazoline N-oxides
3:
DIPEA to form
reaction to α-nitrobenzophenone 4a to form intermediate
Intramolecular cyclization of then delivers which
tautomerizes to . Finally product 6a is formed after water
elimination and aromatization
D which undergoes conjugate addition
Cs2CO3 (130 mg, 0.4 mmol) and hydroquinine derived
thiourea catalyst IV (5.9 mg, 0.01 mmol) were added to solution
of 1 (0.1 mmol) and 2 (0.1 mmol) in Chlorororm (1 mL). Then
water (200 μL) water was added to it. After stirring for 7 days at
RT, 3 mL of water was added. The resulting mixture was extracted
with DCM (3 X 2 mL). The combined organic phase was dried with
Na2SO4, evaporated in vacuum and purified by column
chromatography (15%-20% EtOAc in Hexane) to give compound
3.
E.
F
G
H
.
General procedure for the synthesis of Isoxazole 6:
DIPEA (34 μL, 0.2 mmol) was added to a stirred solution of
4 (0.1 mmol) and 5 (0.1 mmol) in CH3CN (1 mL) and stirring was
maintained at room temperature. After consumption of starting
materials, 3 mL of water was added. The resulting mixture was
extracted with EtOAc (3 X 2 mL). The combined organic phase
was dried with Na2SO4, evaporated in vacuum and purified by
column chromatography (4%-8% EtOAc in hexane) to provide
compound 6.
Acknowledgements
We thank the Central Instruments Facility, Indian Institute of
Technology Guwahati for the instrumental help.
Keywords: Isoxazoline N-oxides; α-Nitrocinnamates;
Organocatalysis; Regioselective; Isoxazoles
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deoxygenation reaction, however
7
via triethylphosphite mediated
decrease in
a
enantioselectivity was observed (Scheme 3)
.
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Conclusion
In summary, we have developed an efficient catalytic
asymmetric synthesis of 3,4,5-trisubstituted isoxazoline N-oxides
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COMMUNICATION
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Title
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Key Topic: Isoxazoles and Isoxazoline-N-oxides
COMMUNICATION
Subas Chandra Sahoo, and Subhas
Chandra Pan *
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Catalytic Enantioselective Synthesis
of 3,4,5-Trisubstituted Isoxazoline N-
oxides and Regioselective Synthesis
of 3,4,5-Trisubstituted Isoxazoles
A convenient catalytic asymmetric synthesis of 3,4,5-trisubstituted isoxazoline N-
oxides and regioselective synthesis of 3,4,5-trisubstituted isoxazoles has been
developed.
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