Harnessing the TEMPO-Catalyzed Aerobic Oxidation for Machetti-De Sarlo Reaction toward Sustainable Synthesis of Isoxazole Libraries

Article abstract of DOI:10.1021/acs.joc.9b01896

A practical synthesis of isoxazole/isoxazoline derivatives via Machetti-De Sarlo reaction under sustainable conditions has been accomplished. This protocol involves the use of readily available 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) to catalyze the

Full text of DOI:10.1021/acs.joc.9b01896

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Article
Harnessing the TEMPO catalyzed aerobic oxidation for Machetti
-DeSarlo reaction towards sustainable synthesis of isoxazole libraries
Murugan Vadivelu, Sugirdha Sampath, Kesavan Muthu, Kesavan Karthikeyan, and Chandrasekar Praveen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01896 • Publication Date (Web): 26 Sep 2019
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Page 1 of 11
The Journal of Organic Chemistry
Harnessing the TEMPO catalyzed aerobic oxidation for Machetti−De
Sarlo reaction towards sustainable synthesis of isoxazole libraries
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a
a,b
c
a
Murugan Vadivelu, Sugirdha Sampath, Kesavan Muthu, Kesavan Karthikeyan,* and Chandrasekar
Praveen*
d,e
aDepartment of Chemistry, B. S. Abdur Rahman Crescent Institute of Science and Technology, Vandalur, Chennai-600048,
Tamil Nadu, India
bDepartment of Metallurgical & Materials Engineering, Indian Institute of Technology-Madras (IITM), Chennai-600036,
Tamil Nadu, India
cInterdisplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology, Kattankulathur-
603203, Tamil Nadu, India
dMaterials Electrochemistry Division, Central Electrochemical Research Institute (CSIR-Laboratory), Alagappapuram,
Karaikudi-630003, Tamil Nadu, India
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eAcademy of Scientific and Innovation Research (AcSIR), CECRI campus, Karaikudi-630003, Alagappapuram, Karaikudi-
6
30003, Tamil Nadu, India
ABSTRACT: A practical synthesis of isoxazole/isoxazoline derivatives via Machetti−De Sarlo reaction under sustainable conditions
has been accomplished. This protocol involves the use of readily available TEMPO to catalyze the cyclocondensation of primary
nitroalkanes with alkynes/alkenes to afford a library of isoxazole/isoxazoline products. From an eco-benign perspective, notable
advantages of this method are (i) water as solvent, (ii) air as oxidant, (iii) transition metal-free, (iv) no base required, (v) no toxic by-
product, (vi) no need of solvent extraction, (vii) diverse substrate scope, (viii) high chemical yields, (ix) excellent chemo- and regi-
oselectivity, (x) short reaction time, (xi) gram-scale synthesis, (xii) extension to heterogeneous version and (xiii) catalyst recyclability.
For these reasons, the developed method is appropriate for safe laboratory use and can be expected to inspire the progress of TEMPO
based organocatalysis for the preparation of isoxazole/isoxazoline moieties in an environmentally benign fashion.
frequently used strategy for isoxazole preparation involves [3+2]
cycloaddition of alkynes with nitrile oxides or through the reac-
tion between hydroxyl amine and a three-carbon component.
INTRODUCTION
3
5
Within these methods, the intermolecular cyclization between
primary nitro compounds and alkynes have received wide atten-
tion, because it builds up isoxazole core in a straightforward
manner without requiring additional synthetic steps (Fig. 1, bot-
tom panel). However, this chemistry requires a strong dehydrat-
ing agent (usually an acylating agent or base) in stoichiometric
Designing practical and eco-benign synthetic methods from sim-
ple precursors with no formation of toxic by-products is of sub-
1
-5
stantial importance in sustainable chemistry. In a similar vein,
chemical transformations performed at aerobic conditions offers
6-8
an added advantage from a green chemistry viewpoint. On the
3
6-41
other hand, chemical processes performed in water has an exten-
sive advantage of both environmental compatibility as well as
proportion and thus possess deleterious effect (eq. 1).
A pro-
gressive work by Machetti and De Sarlo circumvented this limi-
9
42,43
less expensiveness compared to organic solvents. Thus, there
tation by utilizing water as medium.
These particular meth-
has been increasing recognition of water as an attractive medium
odology is quite advantageous for the construction of both isox-
azole as well as isoxazoline frameworks with good functional
group tolerance, yet with the requirement of catalytic amount of
base (DABCO or NaOH), long reaction time and moderate yields
1
0-12
for numerous organic transformations.
To this end, a plethora
of heterocycles such as furans, pyridines, quinolines, indoles, tri-
azines, acridines, pyrazines and pyrimidines have been synthe-
1
3-22
sized in aqueous media.
Likewise, isoxazoles are five-mem-
(
eq. 2). The same team in another endeavor disclosed that similar
4
4
bered nitrogen/oxygen containing heterocycles commonly found
reaction works under Cu(II)/base catalysis. Despite the broad
substrate scope, some minor shortcomings of this method include
low chemical yields, longer reaction time, regioselective issues
and chloroform as solvent (eq. 3). From the background of syn-
in variety of pharmacologically active natural products, clinical
23-27
drugs and lead compounds (Fig 1, top panel).
With no con-
finement to biology, they also finds extensive application as
28, 29
4
5-47
building blocks in synthetic chemistry
rials in optoelectronics.
and as organic mate-
thetic application of Machetti-De Sarlo reaction , it is quite
obvious that a comprehensive green approach addressing the
aforementioned issues for the direct synthesis of isoxazoles is
need of the hour. At this juncture, it is pertinent to mention that
3
0, 31
Because of its unique physical prop-
erties, the construction of this heterocyclic nucleus has continued
3
2-34
to attract the research community for decades.
The most
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organic-nitroxyls catalyzed aerobic oxidation offers perfect plat-
Page 2 of 11
atmospheric dioxygen to effect catalytic-aerobic oxidation.
Therefore, two controlled experiments under the atmosphere of
and N were carried out separately. In case of O , the yield
was quite similar to that obtained under open atmosphere (entry
7). In contrast, the yield was lowered to a greater extent under N
condition (entry 8). These two investigations suggest the possible
role of O acting as co-oxidant in regenerating the TEMPO. To
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form for green synthesis. Especially, 2,2,6,6-tetramethylpiperi-
dine-N-oxyl (TEMPO) possess practical advantages owing to
their water-soluble nature, non-toxicity and less expensiveness
which allows its use as an ideal green oxidant for organic trans-
O
2
2
2
2
4
9-51
formations.
As part of our research direction on sustainable
5
2-56
57, 58
synthesis
and energy,
we envisioned a green chemical ap-
2
proach for the synthesis of isoxazoles synthesis under TEMPO
catalysis. Our working hypothesis is that TEMPO could oxidize
the nitro to nitrile oxide in situ suitable for a sequential 1,3-dipo-
lar cycloaddition reaction with alkynes (eq 4). To the best of our
knowledge, this approach features several green advantages
compared to other procedures and the relevant results are dis-
closed in this paper.
compare the efficacy with TEMPO, other related dialkyl nitrox-
ides were scrutinized under similar conditions (as per entry 4).
The results of which revealed that the reaction with 3-maleimido-
PROXYL (2,2,5,5-tetramethylpyrrolidine-N-oxyl), a pyrroli-
dine-based nitroxide is sluggish to afford poor yield of product
(entry 9). Likewise, structurally simple DTBN (di-tert-butyl ni-
troxide) afforded only moderate yield (entry 10). However, the
bicyclic variants such as 2-azaadamantane N-oxyl (AZADO) and
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-azabicyclononane-N-oxyl (ABNO) afforded products with
yields comparable to that of TEMPO (entries 11 and 12). Despite
the good catalytic potential of these nitroxyls, their cost is too
high compared to TEMPO (ABNO; 250 mg = $ 139, AZADO;
2
50 mg = $ 254, TEMPO; 1g = $ 21, Sigma-Aldrich). Avoiding
high cost is of considerable importance from the perspective of
59
green engineering, thus using TEMPO is quite advantageous
compared to other expensive nitroxyls. N-hydroxyphthalimide
6
0
(NHPI), a much cheaper and widely used organocatalyst in aer-
obic process also produced poor yield of 3a (entry 13). Concern-
ing the overall picture, we validated the best condition as: heating
a mixture of alkyne (1.0 mmoL), nitroalkane (1.5 mmoL) and
o
TEMPO (10 mol%) in water (2 mL) at 60 C for 4 h under open-
air conditions. Under this condition, an array of substrates under-
goes the reaction smoothly and generated the isoxazole products
in good to excellent yields (Chart 1).
Table 1 Optimization studies tested on the synthesis of 3aa
Fig. 1 Pharmacologically active isoxazole molecules (top panel); Cyclocon-
densation Pathways for the synthesis of isoxazole scaffolds (bottom panel)
o
Entry
Organic-nitroxyl T ( C) time Additive
Yield
(%)
b
(mol%)
(h)
24
12
8
RESULTS AND DISCUSSION
1
2
3
4
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (10)
TEMPO (5)
TEMPO (10)
TEMPO (10)
30
60
60
60
60
60
60
60
60
air
air
air
air
air
air
O2
35
81
86
96
49
71
96
18
20
Based on our previous experience of using TEMPO catalysis for
5
5
organo-click reactions, we intended to use the same catalyst for
the present work. We initiated our preliminary investigation
through the prototype synthesis of 3,5-disubstituted isoxazole
4
c
(3a) from ethyl nitroacetate (1a, 1.5 mmol), phenylacetylene (2a,
5
4
1
.0 mmol) and TEMPO (10 mol%) in water (2 mL). At the out-
6
24
4
o
set, a room temperature (30 C) reaction afforded only a moder-
ate yield (35%) of 3a even after 24 h (entry 1). To our delight,
the reaction proceeded well after a double-fold increase in tem-
7
8
9
4
N
2
3-Maleimido-
PROXYL (10)
4
air
o
perature (60 C) to form 3a in 81% yield (entry 2). Though, this
chemistry also works equally in chloroform, we preferred to use
water on the grounds of green chemistry. Based on these initial
observations, we quickly arrived at using TEMPO as catalytic
source for further optimization. Thus, reducing the reaction time
to 8 and 4 h slightly improvised the yield to 86 and 96% respec-
tively (entries 3 and 4). Avoiding water to achieve solvent-free
conditions had a negative influence on the yield which could be
attributed to the inefficient mixing of reactants under neat condi-
tion (entry 5). Moreover, decreasing the catalytic loading from
10 to 5 mol% required longer reaction time for the completion of
reaction with notable diminution in yield (entry 6). It is to be re-
membered that all the tested reactions were performed under
open-flask conditions, which could result in the participation of
10
11
12
13
DTBN (10)
AZADO (10)
ABNO (10)
NHPI (10)
60
60
60
60
4
4
4
4
air
air
37
95
91
28
Air
Air
a
All tested reactions were performed using 1.5 mmol of 1a and 1.0
b
c
mmol of 2a; Isolated yield of product 3a; Solvent-free condition
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could be because of the slow deprotonation of CH
As the first part of substrate variation, different terminal acety-
3
2
NO under
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lenes such as arylalkynes, propargyloxy aromatics and aliphatic
alkynes were reacted with ethyl nitroacetate under the optimized
conditions. All of these alkynes furnished the desired 3,5-disub-
stituted isoxazoles (3a, 3b, 3d, 3e and 3u) in excellent yields
aqueous condition (pKa = 11). Nevertheless, the scope of the
current green methodology is quite comprehensive to accommo-
date a wide range of substrates of different electronic nature. In
terms of simplicity and practicality, the developed protocol
seems to be superior compared to some of the literature prece-
(
>90 %). However, products (3c, 3f and 3g) derived from alkynes
6
2-67
possessing deactivating substituents like -C , -NO and -CN
6
F
5
2
dents for the combinatorial synthesis of isoxazoles.
The
were obtained in slightly reduced yields (85-89%), which could
be reasoned to the created electron deficiency around the alkyne
unit. However, other substrates including benzoylnitromethane
and methyl nitroacetate reacts with equal efficiency towards
electronically distinguishable alkynes as exemplified by the ex-
cellent chemical yields (90-96%) of 3h-3s. The overall process
is regiocontrolled, since 3,5-disubstituted isoxazoles are formed
as sole isomers with no formation of theoretically possible 3,4-
disubstituted isomers. It is noteworthy to mention, that alkyne
substrates having silyl and amide tether tolerated well under the
standard reaction conditions to form the functionalized isoxa-
zoles 3v and 3w respectively. The optimized conditions were
also found to be amenable to alkynes holding hydroxyl function-
ality (3x and 3y). Notably, 3x having a primary alcohol was iso-
lated as the sole product without over-oxidization via TEMPO
catalysis, signifying the mildness of our oxidative conditions. In-
stead of nitro derivatives possessing active methylene group, a
structure of all products was thoroughly characterized by FT-IR,
H NMR, C NMR, and HRMS techniques. As an illustrative
1
13
example, the FT-IR of 3k displayed an absorbance band at 1660
-1
cm characteristic of the C=N stretching of the isoxazole nu-
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cleus. In H NMR recorded as CDCl
3
solution, two singlets at δ
2
5.21 and 6.87 ppm corresponds to the protons of the -OCH -
1
3
group and C4-H of the isoxazolyl ring respectively. In C NMR
spectrum, sharp peaks at δ 61.8 and 185.4 ppm individually ap-
proves to the -OCH - and C=O carbons. A peak at δ 104.5 ppm
2
is typical of the C4 carbon of the isoxazolyl ring. HRMS analysis
exhibited a peak at m/z(obs.) = 297.0810 corresponds to the mo-
+
lecular ion [M] is in good agreement with the expected
m/z(expd.) = 297.0801. Finally, X-ray diffraction analysis of sin-
gle crystals obtained after recrystallization from chloroform so-
lution unambiguously established the structure of 3k (CCDC
68
1813138).
3 2
test reaction with CH NO completely failed to proceed. This
Chart 1 Synthesized isoxazole libraries (3a-3y) in aerobic oxidative conditions under TEMPO catalysis
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Scheme 1 a) Scale-up reaction; b) Synthetic elaboration to olefins; and c) internal alkynes
To showcase the synthetic applicability of our procedure, a
gram-scale synthesis of 3a in 2.02 g was accomplished (Scheme
1a). To further explore the generality of the current protocol,
olefins instead of alkynes were reacted with ethyl/methyl nitro-
acetate 1a-b under similar conditions (Scheme 1b). Indeed, the
reaction worked well with styrene (4a) and methyl acrylate (4b)
2
to give Δ -isoxazolines (5a-d) in moderate to good yield of 62,
9, 77 and 78% respectively. Nevertheless, this slightly reduced
6
yield could possibly because of the lesser electron density of the
2
3
sp -carbon compared to the sp -carbon of alkyne surrogates. In
a similar manner, cyclic olefin in the form of N-methylmalei-
mide (4c) also undergoes cyclo-condensation with 1a affording
the bicyclic isoxazoline (5e) in 50% yield. It is appropriate to
2
mention that Δ -isoxazolines tend to undergo oxidation to the
6
9-71
corresponding isoxazoles.
However, the isoxazolines (5a-e)
formed does not undergo in situ oxidation to isoxazoles clearly
signifies the mild nature of our reaction conditions. On the other
hand, symmetrical internal alkynes such as diethyl acetylenedi-
carboxylate (6a) and dimethyl acetylenedicarboxylate (6b)
yielded the corresponding 3,4,5-trisubstituted isoxazole (7a-c)
in moderate, yet synthetically acceptable yields (Scheme 1c).
Here too, the reduced electron density at the alkyne carbons by
3
electron withdrawing -COOR groups is reasoned to the low
7
2
chemical yield.
Scheme 2 Control experiments for mechanistic understanding
To gain insight into the mechanism, it is noteworthy to mention
that the nitrile-oxide mechanism is validated in an event of in-
termolecular addition–elimination of ethyl nitroacetate (1a) to
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form 3,4-bis(ethoxycarbonyl)-1,2,5-oxadiazole 2-oxide (3a')
under DABCO catalysis following the literature procedure
(Table 2). Gratifyingly, the use of PS-TEMPO under the opti-
mized conditions resulted in 3a in an excellent yield of 95%,
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4, 73
(Scheme 2, top panel).
When we attempted the same reac-
which is as comparable to the yield from free TEMPO (96%).
4
2
tion using TEMPO instead of DABCO leads to the quantitative
recovery of starting material 1a with no formation of 3a'
Comparatively, the same product by DABCO catalysis was
reported to be obtained in 69% only after 18 h, thus signifies the
efficiency of the developed protocol. After completion of the
reaction, PS-TEMPO was removed from the reaction mixture
by simple centrifugation, washed with water followed by pre-
(Scheme 2, middle panel). This observation clearly excludes the
possibility of generation of nitrile oxide intermediates during
the reaction course, therefore, must involve a different mecha-
nism under TEMPO conditions. When the reaction between 1a
o
cooled ethanol. Subsequent drying at 80 C for 2 h affords the
and 2a was carried out at standard conditions by replacing H
2
O
recovered PS-TEMPO, which can be used directly for more cat-
alytic runs without further activation. The recuperated PS-
TEMPO can be used up to six catalytic cycles with almost neg-
ligible decrease in yield and conversion after each cycle. Ac-
cordingly, the catalyst recyclability studies evidently highlight
the attractiveness of the developed protocol from the viewpoint
of green chemistry.
with D O, no deuterium incorporated product (3a-D) was ob-
2
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served and only 3a was obtained (Scheme 2, bottom panel).
Since none of deuterium incorporation was detected in the prod-
uct, it attributes to the non-intervention of water via proton ex-
change in the reaction. It is also to be remembered that the yield
of 3a is significantly reduced to 18% under N
per Table 1, entry 8), which obviously testifies the involvement
of O in the reaction. From all the above remarks from control
2
atmosphere (as
2
Table 2 Recycling experiments tested on heterogeneously im-
experiments, a tentative mechanism was proposed (Scheme 3).
a
mobilized TEMPO
According to which, TEMPO undergoes a one electron oxida-
74
2
tion in the presence of O to form N-oxoammonium ion A.
This was followed by the nucleophilic attack of oxygen of -NO
2
group to the quaternary nitrogen of A to generate intermediate
B. Subsequently, the oxygen anion of B abstracts the α-hydro-
gen to form a nitrone-type 1,3-dipole intermediate C. As a con-
sequence, the latter undergoes cycloaddition with alkyne to
form the cyclic intermediate D. Another abstraction of α-hydro-
gen leads to the formation of isoxazole along with intermediate
E. Proton transposition of latter results in intermediate F suita-
ble for further dehydration to regenerate TEMPO.
Catalytic
cycle
Catalyst re-
covery (%)
Conversion Isolated yield
b
(%)
>99
>99
97
(%)
95
94
92
91
91
90
1
2
3
4
100
100
99
99
98
97
95
c
5
6
98
94
a1.5 mmol of 1a, 1.0 mmol of 2a, 10 mol% of PS-TEMPO (100
mg of 1.0 mmol/g loading) and water (2 mL) at open air condi-
b
tion; Conversion monitored by crude NMR analysis and >99%
indicates no remaining of 2a.
In summary, a simple and safe laboratory procedure for the
preparation of isoxazoles/isoxazolines by adopting Ma-
chetti−De Sarlo chemistry from commercially viable and inex-
pensive starting materials were accomplished. The key feature
of this chemistry is the use of catalytic amounts of TEMPO as
non-toxic oxidant to promote the oxidative cycloaddition step
in aqueous medium. The practical feasibility of this method is
validated through the synthesis of structurally diverse isoxazole
derivatives. From the perspective of synthetic chemistry, the ad-
vantages include high chemical yields, wide substrate scope,
gram-scale synthesis, excellent regioselectivity, operational
simplicity and short reaction time. The process also encom-
passes several eco-friendly aspects such as open-air conditions,
water as solvent, no toxic by product, no solvent extraction,
base and transition-metal free. Another sustainable advantage is
the ease with which the reaction works equally well in hetero-
geneous conditions in presence of polymer supported TEMPO.
In the latter case, the heterogeneous catalyst can be easily recu-
perated and reused for six catalytic cycles without significant
loss in activity. On a whole, the present study demonstrates the
dexterity of TEMPO as green catalytic oxidant for the synthesis
of isoxazole libraries under green conditions. The application of
Scheme 3 Proposed mechanism for the formation of isoxazoles
under TEMPO catalyzed aerobic oxidation
At this point of our investigation, we became interested on the
heterogeneous version of our chemistry, because of the foreseen
advantage of catalyst recovery after the reaction. Hence, we
chose commercially available polymer immobilized TEMPO
(PS-TEMPO, 1.0 mmol/g loading) for the model reaction
5
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The Journal of Organic Chemistry
Page 6 of 11
this sort of chemistry for the sustainable synthesis of other het-
ero- and carbocycles are actively underway in our laboratory.
Ethyl 5-phenylisoxazole-3-carboxylate (3a).76 White solid; 205
mg (96%), R = 0.56 (20% Ethylacetate : n-Hexane); Mp 47-49
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
f
o
76
o
C (lit. 48-49 C); FT-IR (neat): υ = 1726, 1613, 1476, 1441
-1 1
EXPERIMENTAL SECTION
General methods and materials
3
cm ; H NMR (400 MHz, CDCl ): δ (ppm) 7.82-7.80 (m, 2H),
7
.49-7.48 (m, 3H), 6.93 (s, 1H), 4.48 (q, J = 8.0 Hz, 2H), 1.44
1
3
1
3
(t, J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ (ppm)
All chemicals and solvents were purchased from Sisco Re-
search Laboratories and Alfa Aesar Pvt. Ltd. PS-TEMPO (100-
171.7, 160.0, 156.9, 130.8, 129.1, 126.7, 125.9, 99.9, 62.2, 14.2.
2
00 mesh, 1.0 mmol/g loading, 1% cross-linked with divi-
Ethyl 5-((2,6-dichlorophenoxy)methyl)isoxazole-3-carboxylate
nylbenzene) was purchased from Sigma-Aldrich Pvt. Ltd. In-
frared (IR) spectra for all compounds were recorded as neat by
Attenuated Total Reflectance (ATR) mode on a JASCO 6300
FTIR spectrometer. Column chromatography was performed
using thick-walled glass columns along with a mixture of petro-
leum ether and ethyl acetate on silica gel (100-200 mesh, SRL,
India). The relative proportions of solvents in chromatography
solvent mixtures refer to the volume to volume ratio. Analytical
TLC was performed on precoated plastic sheets of silica gel
G/UV-254 of 0.2 mm thickness (Macherey-Nagel, Germany)
using analytical grade solvents and visualized with iodine spray
(3b). White solid; 288 mg (92%), R
f
= 0.47 (20% Ethylacetate
o
: n-Hexane); Mp 79-81 C; FT-IR (neat): υ = 1765, 1628, 1489,
-1 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1432 cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 7.33 (d, J =
8.0 Hz, 2H), 7.09-7.05 (m, 1H), 6.87 (s, 1H), 5.22 (s, 2H), 4.46
1
3
1
(q, J = 8.0 Hz, 2H), 1.43 (t, J = 8.0 Hz, 3H); C{ H} NMR (100
MHz, CDCl ): δ (ppm) 169.1, 159.7, 156.5, 150.2, 129.5, 129.2,
126.2, 104.9, 64.8, 62.3, 14.2; HRMS (EI-Quadrupole): m/z =
3
+
2 4
315.0064, calcd. for C13H11Cl NO (M ): 315.0065.
Ethyl
5-((perfluorophenoxy)methyl)isoxazole-3-carboxylate
= 0.44 (20% Ethylacetate :
(3c). White solid; 135 mg (89%), R
f
o
-1 1
n-Hexane); Mp 62-64 C; FT-IR (neat): υ = 1731 cm ; H NMR
400 MHz, CDCl ): δ (ppm) 6.83 (s, 1H), 5.32 (s, 2 H), 4.46 (q,
J = 8.0 Hz, 2H), 1.43 (t, J = 8.0 Hz, 3H); C{ H} NMR (100
MHz, CDCl ): δ (ppm) 167.9, 159.4, 156.6, 143.1, 140.5, 139.3,
136.8, 105.2, 66.1, 62.5, 14.1; HRMS (EI-Quadrupole): m/z =
(
10% w/w I
alkaline KMnO
open capillaries and are uncorrected. H and C NMR spectra
were recorded in deuterated chloroform (CDCl ) using Bruker
2
in silica gel), UV light (λ = 254 and 365 nm) and
(
3
4
solution.All melting points were measured on
1
3
1
1
13
3
3
1
13
spectrometer ( H NMR: 400 and 500 MHz; C NMR: 100 and
125 MHz). Proton chemical shifts (δ) are relative to tetrame-
thylsilane (TMS, δ = 0.00) as an internal standard and are ex-
pressed in parts per million (ppm). The number of protons (n)
for a given resonance is indicated as nH. Spin multiplicities are
given as s (singlet), d (doublet), t (triplet), q (quartet), and m
+
3
8 5 4
37.0371, calcd. for C13H F NO (M ): 337.0373.
Ethyl 5-(m-tolyl)isoxazole-3-carboxylate (3d). White solid; 375
mg (94%), R = 0.61 (20% Ethylacetate : n-Hexane); Mp 56-58
f
o
-1 1
C; FT-IR (neat): υ = 1762 cm ; H NMR (400 MHz, CDCl
δ (ppm) 7.62-7.59 (m, 2H), 7.37 (t, J = 8.0 Hz, 1H), 7.28 (d, J
8.0 Hz, 1H), 6.90 (s, 1H), 4.47 (q, J = 8.0 Hz, 2H), 2.42 (s,
3
):
(multiplet). Coupling constants (J) are given in hertz (Hz). Mass
=
spectra were recorded on a JEOL GC Mate (II) using electron
impact ionization (EI-Quadrupole) and Micromass (ESI-
QTOF) spectrometer technique.
1
3
1
3
3H), 1.44 (t, J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ):
δ (ppm) 171.9, 160.1, 156.9, 138.9, 131.6, 129.0, 126.6, 126.5,
123.1, 99.8, 62.2, 21.4, 14.2; HRMS (EI-Quadrupole): m/z =
+
2
31.0894, calcd. for C13
H13NO
3
(M ): 231.0895.
Typical procedure for the preparation of isoxazoles (3a-3u):
Ethyl
5-((4-fluorophenoxy)methyl)isoxazole-3-carboxylate
= 0.41 (20% Ethylacetate :
A mixture of nitroalkane 1a-c (1.5 mmoL), alkyne 2a-m or 6a-
b (1.0 mmoL), TEMPO (10 mol%) and water (2 mL) were
(3e). White solid; 320 mg (91%), R
f
o
-1 1
n-Hexane); Mp 63-65 C; FT-IR (neat): υ = 1735 cm ; H NMR
(400 MHz, CDCl ): δ (ppm) 7.02-6.98 (m, 2H), 6.92-6.88 (m,
2H), 6.74 (s, 1H), 5.17 (s, 2H), 4.44 (q, J = 8.0 Hz, 2H), 1.41 (t,
o
heated to 60 C (oil bath) with vigorous stirring in an open tube
3
for 4 h. Upon completion of the reaction as indicated by TLC,
water was removed under reduced pressure. To this residue,
ethyl acetate (5 mL) was added and dried over anhydrous
Na SO . The solvent was concentrated under reduced pressure
2 4
to obtain the crude product, which was further purified by a
short silica gel flash chromatography to obtain pure product of
1
3
1
3
J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ (ppm)
169.7, 159.6, 158.0 (d, J = 238.8 Hz), 156.6, 153.6 (d, J = 2.2
Hz), 116.2 (d, J = 23.2 Hz), 116.1 (d, J = 8.1 Hz), 104.0, 62.3,
61.8, 14.1; HRMS (EI-Quadrupole): m/z = 265.0752, calcd. for
+
C
13
H12FNO
4
(M ): 265.0750.
3
a-3y and 7a-7c.
Ethyl 5-((4-nitrophenoxy)methyl)isoxazole-3-carboxylate (3f).
White solid; 280 mg (85%), R = 0.24 (20% Ethylacetate : n-
Typical procedure for the preparation of isoxazolines (5a-
c):
f
o
-1 1
5
Hexane); Mp 121-123 C; FT-IR (neat): υ = 1762 cm ; H NMR
400 MHz, CDCl ): δ (ppm) 8.26-8.23 (m, 2H), 7.07-7.05 (m,
2H), 6.82 (s, 1H), 5.32 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H), 1.43 (t,
(
3
A mixture of nitroalkane 1a-b (1.5 mmoL), styrene/methylacry-
late/N-methylmaleimide 4a-c (1.0 mmoL), TEMPO (10 mol%)
1
3
1
3
J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl ): δ (ppm)
o
and water (2 mL) was heated to 60 C (oil bath) with vigorous
168.2, 162.2, 159.5, 156.7, 142.5, 126.1, 114.8, 104.6, 62.5,
stirring in an open tube for 4 h. Upon completion of the reaction
as indicated by TLC, water was removed under reduced pres-
sure. To this residue, ethyl acetate (5 mL) was added and dried
61.2, 14.1; HRMS (EI-Quadrupole): m/z = 292.0695, calcd. for
+
C
13
H
12
N
2
O
6
(M ): 292.0695.
over anhydrous Na
2
SO
4
. The solvent was concentrated under
Ethyl
5-((4-cyanophenoxy)methyl)isoxazole-3-carboxylate
= 0.19 (20% Ethylacetate
reduced pressure to obtain the crude product, which was further
purified by a short silica gel flash chromatography to obtain
pure product of 5a-5e.
(3g). White solid; 300 mg (86%), R
f
o
-1 1
: n-Hexane); Mp 112-114 C; FT-IR (neat): υ = 1736 cm ; H
NMR (400 MHz, CDCl ): δ (ppm) 7.65-7.62 (m, 2H), 7.05-7.02
m, 2H), 6.79 (s, 1H), 5.27 (s, 2H), 4.46 (q, J = 8.0 Hz, 2H),
3
(
1
3
1
1.42 (t, J = 8.0 Hz, 3H); C{ H} NMR (100 MHz, CDCl
3
): δ
6
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Page 7 of 11
The Journal of Organic Chemistry
(
ppm) 168.4, 160.6, 159.5, 156.7, 134.3, 118.7, 115.4, 105.6, (5-((Naphthalen-2-yloxy)methyl)isoxazol-3-yl)(Phenyl)meth-
7
5
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
104.5, 62.5, 60.9, 14.1; HRMS (EI-Quadrupole): m/z =
272.0799, calcd. for C14
anone (3n). White solid; 150 mg (91%), R
= 0.59 (20%
f
75
+
o
o
H
12
N
2
O
4
(M ): 272.0797.
Ethylacetate : n-Hexane); Mp 111-113 C (lit. 110-111 C);
-1 1
FT-IR (neat): υ = 1694, 1609, 1461 cm ; H NMR (400 MHz,
Phenyl (5-phenylisoxazol-3-yl)methanone (3h).44 White solid;
CDCl ): δ (ppm) 8.31-8.29 (m, 2H), 7.80-7.74 (m, 3H), 7.65 (t,
3
2
7
20 mg (90%), R
f
= 0.76 (20% Ethylacetate : n-Hexane); Mp
J = 8.0 Hz, 1H), 7.53-7.44 (m, 3H), 7.40-7.38 (m, 1H), 7.25-
o
44
o
-1
1
13
1
8-80 C (lit. 84-85 C); FT-IR (neat): υ = 1665, 1453 cm ; H
): δ (ppm) 8.36-8.34 (m, 2H), 7.86-7.84
m, 2H), 7.66-7.64 (m, 1H), 7.56-7.49 (m, 5H), 7.05 (s, 1H);
7.20 (m, 2H), 6.92 (s, 1H), 5.35 (s, 2H); C{ H} NMR (100
NMR (400 MHz, CDCl
3
MHz, CDCl ): δ (ppm) 185.4, 168.8, 161.9, 155.6, 135.6, 134.3,
3
(
134.1, 130.7, 129.9, 129.5, 128.6, 127.8, 126.9, 126.7, 124.3,
118.5, 107.4, 104.5, 61.1.
13
1
C{ H} NMR (100 MHz, CDCl
3
): δ (ppm) 185.8, 170.8, 162.5,
1
35.8, 134.1, 130.8, 130.7, 129.2, 128.6, 126.7, 126.0, 100.3.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phenyl (5-(m-tolyl)isoxazol-3-yl) methanone (3o). White solid;
(5-((2,6-Dichlorophenoxy)methyl)isoxazol-3-yl)(phenyl)meth-
anone (3i). White solid; 159 mg (92%), R = 0.66 (20%
Ethylacetate : n-Hexane); Mp 139-141 C; FT-IR (neat): υ =
210 mg (93%), R = 0.80 (20% Ethylacetate : n-Hexane); Mp
f
o
-1
1
f
84-86 C; FT-IR (neat): υ = 1644 cm ; H NMR (400 MHz,
o
CDCl ): δ (ppm) 8.36-8.33 (m, 2H), 7.67-7.63 (m, 3H), 7.55-
3
-
1 1
1
2
2
655 cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 8.32-8.29 (m,
7.52 (m, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H),
1
3
1
H), 7.67-7.63 (m, 1H), 7.55-7.51 (m, 2H), 7.33 (d, J = 8.0 Hz,
7.03 (s, 1H), 2.44 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ
3
(ppm) 185.9, 171.0, 162.4, 138.9, 135.8, 134.0, 131.5, 130.7,
129.1, 128.6, 126.7, 126.6, 123.2, 100.1, 21.4; HRMS (EI-
1
3
1
H), 7.08-7.06 (m, 1H), 6.96 (s, 1H), 5.26 (s, 2H); C{ H}
): δ (ppm) 185.5, 168.0, 161.9, 150.3,
35.7, 134.1, 130.7, 129.6, 129.2, 128.6, 126.1, 105.3, 64.7;
HRMS (EI-Quadrupole): m/z 347.0114, calcd. for
NMR (100 MHz, CDCl
1
3
+
Quadrupole): m/z = 263.0946, calcd. for C H NO (M ):
1
7
13
2
=
263.0946.
+
17 2 3
C H11Cl NO (M ): 347.0116.
Methyl 5-phenylisoxazole-3-carboxylate (3p). White solid;
(5-((Perfluorophenoxy)methyl)isoxazol-3-yl)(phenyl)meth-
anone (3j). White solid; 160 mg (96%), R = 0.68 (20%
Ethylacetate : n-Hexane); Mp 64-65 C; FT-IR (neat): υ = 1660
180mg (91%), R = 0.57 (20% Ethylacetate : n-Hexane); Mp
f
o
-1
1
f
68-70 C; FT-IR (neat): υ = 1720 cm ; H NMR (400 MHz,
o
CDCl ): δ (ppm) 7.74-7.72 (m, 2H), 7.42-7.40 (m, 3H), 6.86 (s,
3
-1
1
13
1
cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 8.31-8.28 (m, 2H),
1H), 3.93 (s, 3H); C{ H} NMR (100 MHz, CDCl ): δ (ppm)
3
7
.69-7.64 (m, 1H), 7.55-7.52 (m, 2H), 6.94 (s, 1H), 5.36 (s, 2H);
C{ H} NMR (100 MHz, CDCl ): δ (ppm) 185.1, 166.9, 161.9,
3
43.0, 140.7, 139.3, 136.8, 135.4, 134.3, 132.1, 130.7, 128.7,
171.8, 160.5, 156.7, 130.9, 129.2, 126.6, 125.9, 99.9, 52.9;
HRMS (EI-Quadrupole): m/z = 203.0582, calcd. for C H NO
3
(M ): 203.0582.
1
3
1
1
1
9
+
1
1
05.6, 66.1; HRMS (EI-Quadrupole): m/z = 369.0422, calcd.
+
for C17
H
8
F
5
NO
3
(M ): 369.0424.
Methyl 5-(m-tolyl)isoxazole-3-carboxylate (3q). White solid;
175 mg (94%), R = 0.63 (20% Ethylacetate : n-Hexane); Mp
f
o
-1 1
(5-((4-Fluorophenoxy)methyl)isoxazol-3-yl)(phenyl)meth-
anone (3k). White solid; 187 mg (94%), R = 0.65 (20%
Ethylacetate : n-Hexane); Mp 99-101 C; FT-IR (neat): υ =
1
2
6
120-122 C; FT-IR (neat): υ = 1724 cm ; H NMR (400 MHz,
f
CDCl ): δ (ppm) 7.55-7.52 (m, 2H), 7.30 (t, J = 8.0 Hz, 1H),
3
o
7.22-7.19 (m, 1H), 6.83 (s, 1H), 3.93 (s, 3H), 2.35 (s, 3H);
-1
1
13
1
660 cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 8.31-8.29 (m,
3
C{ H} NMR (100 MHz, CDCl ): δ (ppm) 172.1, 160.6, 156.7,
H), 7.68-7.63 (m, 1H), 7.54-7.51 (m, 2H), 7.04-6.99 (m, 2H),
139.1, 131.7, 129.1, 126.6, 123.2, 99.9, 52.9, 21.5; HRMS (EI-
1
3
1
+
.95-6.92 (m, 2H), 6.87 (s, 1H), 5.21 (s, 2H); C{ H} NMR
): δ (ppm) 185.4, 168.6, 161.9, 157.9 (d, J =
Quadrupole): m/z = 217.0737, calcd. for C H NO (M ):
1
2
11
3
(100 MHz, CDCl
3
217.0739.
2
1
38.7 Hz), 153.7 (d, J = 2.2 Hz), 135.6, 134.2, 130.7, 128.6,
16.2 (d, J = 23.2 Hz), 116.1 (d, J = 8.0 Hz), 104.5, 61.8; HRMS
Methyl 5-((2,6-dichlorophenoxy)methyl)isoxazole-3-carbox-
ylate (3r). White solid; 135 mg (90%), R = 0.47 (20%
Ethylacetate : n-Hexane); Mp 80-82 C; FT-IR (neat): υ = 1725
(EI-Quadrupole): m/z = 297.0810, calcd. for C17
297.0801.
H12FNO
3
(M+):
f
o
-1 1
cm ; H NMR (400 MHz, CDCl
3
): δ (ppm) 7.29-7.24 (m, 2H),
(5-((4-Nitrophenoxy)methyl)isoxazol-3-yl)(phenyl)methanone
7.01-6.97 (m, 1H), 6.80 (s, 1H), 5.15 (s, 2H), 3.92 (s, 3H);
1
3
1
(3l). White solid; 170 mg (93%), R = 0.42 (20% Ethylacetate :
f
3
C{ H} NMR (100 MHz, CDCl ): δ (ppm) 169.3, 160.3, 156.3,
o
-1
1
n-Hexane); Mp 136-138 C; FT-IR (neat): υ = 1647 cm ; H
NMR (400 MHz, CDCl ): δ (ppm) 8.32-8.24 (m, 4H), 7.69-7.65
m, 1H), 7.56-7.52 (m, 2H), 7.10-7.06 (m, 2H), 6.94 (s, 1H),
150.3, 129.6, 129.3, 126.2, 104.9, 64.8, 53.0; HRMS (EI-
Quadrupole): m/z = 300.9908, calcd. for C H Cl NO (M ):
+
3
1
2
9
2
4
(
300.9909.
13
1
5
1
1
3
.35 (s, 2H); C{ H} NMR (100 MHz, CDCl ): δ (ppm) 185.1,
67.2, 162.3, 162.0, 142.5, 135.4, 134.3, 130.7, 128.7, 126.1,
Methyl 5-((perfluorophenoxy)methyl)isoxazole-3-carboxylate
(3s).White solid; 131 mg (90%), R = 0.52 (20% Ethylacetate :
14.8, 105.0, 61.2; HRMS (EI-Quadrupole): m/z = 324.0748,
f
+
o
-1 1
calcd. for C17
H
12
N
2
O
5
(M ): 324.0746.
n-Hexane); Mp 60-62 C; FT-IR (neat): υ = 1732 cm ; H NMR
(400 MHz, CDCl ): δ (ppm) 6.76 (s, 1H), 5.24 (s, 2H), 3.92 (s,
3
1
3
1
4
-((3-Benzoylisoxazol-5-yl)methoxy)benzonitrile (3m). White
3H); C{ H} NMR (100 MHz, CDCl ): δ (ppm) 167.9, 159.8,
3
o
solid; Mp 118-120 C; 185 mg (96%), R
Ethylacetate : n-Hexane); FT-IR (neat): υ = 1660 cm ; H NMR
400 MHz, CDCl ): δ (ppm) 8.31-8.29 (m, 2H), 7.68-7.62 (m,
H), 7.55-7.51 (m, 2H), 7.08-7.04 (m, 2H), 6.91 (s, 1H), 5.30
f
= 0.44 (20%
156.4, 142.9, 140.6, 139.1, 136.7, 105.2, 66.1, 53.0; HRMS (EI-
-1
1
+
Quadrupole): m/z = 323.0217, calcd. for C H F NO (M ):
1
2
6
5
4
(
3
3
323.0217.
13
1
(s, 2H); C{ H} NMR (100 MHz, CDCl
3
): δ (ppm) 185.1,
67.4, 161.9, 160.7, 135.5, 134.3, 134.2, 130.7, 128.7, 118.7,
15.5, 105.6, 104.9, 60.9; HRMS (EI-Quadrupole): m/z =
Methyl 5-((4-fluorophenoxy)methyl)isoxazole-3-carboxylate
(3t). White solid; 153 mg (91%), R = 0.39 (20% Ethylacetate :
n-Hexane); Mp 82-84 C; FT-IR (neat): υ = 1724 cm ; H NMR
1
1
f
o
-1 1
+
304.0848, calcd. for C18
H
12
N
2
O
3
(M ): 304.0848.
(400 MHz, CDCl
3
): δ (ppm) 7.02-6.98 (m, 2H), 6.92-6.88 (m,
7
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The Journal of Organic Chemistry
Page 8 of 11
1
3
1
Methyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate (5b).76
Clear oil; 130 mg (69%), R = 0.34 (20% Ethylacetate : n-Hex-
ane); FT-IR (neat): υ =; 1715, 1598 cm ; H NMR (500 MHz,
CDCl ): δ (ppm) 7.39-7.31 (m, 5H), 5.78 (dd, J = 11.5, 9.0 Hz,
1H), 3.89 (s, 3H), 3.64 (dd, J = 18.0, 11.5 Hz, 1H), 3.22 (dd, J
2
H), 6.75 (s, 1H), 5.17 (s, 2H), 3.98 (s, 3H); C{ H} NMR (100
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl
): δ (ppm) 169.8, 160.1, 158.0 (d, J = 238.8 Hz),
156.3, 153.6 (d, J = 2.2 Hz), 116.2 (d, J = 23.2 Hz), 116.1 (d, J
= 8.1 Hz), 104.0, 61.8, 52.9; HRMS (EI-Quadrupole): m/z =
3
f
-1 1
3
+
2
51.0592, calcd. for C12
H10FNO
4
(M ): 251.0594.
1
3
1
=
3
18.0, 9.0 Hz, 1H); C{ H} NMR (125 MHz, CDCl ): δ (ppm)
Ethyl 5-decylisoxazole-3-carboxylate (3u). Clear oil; 312 mg
92%), R = 0.52 (20% Ethylacetate : n-Hexane); FT-IR (neat):
υ = 1719, 1590 cm ; H NMR (500 MHz, CDCl
160.9, 150.9, 139.4, 128.9, 128.7, 125.8, 85.0, 52.8, 41.3.
(
f
-1
1
3
): δ (ppm) 6.33
s, 1H), 4.37-4.35 (m, 2H), 2.73-2.70 (m, 2H), 1.66-1.61 (m,
3-Ethyl 5-methyl 4,5-dihydroisoxazole-3,5-dicarboxylate
77
(
(5c). Clear oil; 180 mg (77%), R
f
= 0.30 (20% Ethylacetate :
-1
1
3
H), 1.35-1.32 (m, 4H), 1.25-1.18 (m, 12H), 0.82-0.79 (m, 3H);
n-Hexane); FT-IR (neat): υ =1724, 1719, 1591 cm ; H NMR
(500 MHz, CDCl ): δ (ppm) 5.22 (dd, J = 11.0, 8.0 Hz, 1H),
4.36 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.52-3.49 (m, 2H), 1.38
1
3
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C{ H} NMR (125 MHz, CDCl
): δ (ppm) 175.7, 160.2, 156.3,
3
3
101.4, 61.9, 31.8, 29.5, 29.4, 29.3, 29.1, 28.9, 27.4, 26.7, 22.6,
1
3
1
14.1, 14.0; HRMS (EI-Quadrupole): m/z = 281.1989, calcd. for
3
(t, J = 7.0 Hz, 3H); C{ H} NMR (125 MHz, CDCl ): δ (ppm)
+
C
16
H
27NO
3
(M ): 281.1991.
169.4, 159.8, 151.1, 79.7, 62.4, 53.0, 37.6, 14.1.
7
5
Dimethyl 4,5-dihydroisoxazole-3,5-dicarboxylate (5d).77 Clear
oil; 170 mg (78%), R = 0.34 (20% Ethylacetate : n-Hexane);
FT-IR (neat): υ =1728, 1714, 1597 cm ; H NMR (500 MHz,
CDCl ): δ (ppm) 5.22 (dd, J = 11.5, 8.0 Hz, 1H), 3.90 (s, 3H),
3.82 (s, 3H), 3.53-3.49 (m, 2H); C{ H} NMR (125 MHz,
Phenyl(5-(trimethylsilyl)isoxazol-3-yl)methanone (3v). White
o
o
solid; Mp 33-35 C (lit. 32-34 C); 145mg (71%), R
f
= 0.88
f
-1
1
(
1
20% Ethylacetate : n-Hexane); FT-IR (neat): υ = 3141, 2960,
-1
1
665, 1590 cm ; H NMR (500 MHz, CDCl
3
): δ (ppm) 8.31
3
13
1
(
dd, J = 8.5, 1.5 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.52 (t, J =
1
3
1
7
.5 Hz, 2H), 6.97 (s, 1H), 0.41 (s, 9H); C{ H} NMR (125
): δ (ppm) 186.4, 179.4, 160.4, 136.2, 134.0, 130.8,
128.6, 113.6, -1.82.
CDCl
37.6.
3
): δ (ppm) 169.3, 160.2, 150.9, 79.8, 79.8, 53.1, 53.0,
MHz, CDCl
3
Methyl
5-methyl-4,6-dioxo-4,5,6,6a-tetrahydro-3aH-pyr-
7
8
3
-Benzoyl-N-methylisoxazole-5-carboxamide (3w). White
rolo[3,4-d]isoxazole-3-carboxylate (5e). White solid; Mp
207-209 C (lit. 205-208 C); 95 mg (50%), R
o
o
o
solid; Mp 142-144 C; 174 mg (63%), R
f
= 0.43 (50%
f
= 0.30 (50%
-1
-1
Ethylacetate : n-Hexane); FT-IR (neat): υ = 1732, 1625 cm ;
Ethylacetate : n-Hexane); FT-IR (neat): υ = 1726, 1698 cm ;
1
1
H NMR (500 MHz, CDCl
3
): δ (ppm) 8.26 (dd, J = 8.5, 1.0 Hz,
H NMR (500 MHz, DMSO-d
6
): δ (ppm) 5.68 (d, J = 9.5 Hz,
13
1
2
6
H), 7.69-7.65 (m, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.38 (s, 1H),
1H), 4.80 (d, J = 9.5 Hz, 1H), 3.84 (s, 3H), 2.87 (s, 3H); C{ H}
13
1
.88 (br-s, 1H), 3.06 (d, J = 5.0 Hz, 3H); C{ H} NMR (125
): δ (ppm) 184.7, 164.0, 162.4, 155.9, 135.3, 134.4,
130.6, 128.7, 107.6, 26.4. HRMS (ESI-QTOF): m/z = 231.0757,
NMR (125 MHz, DMSO-d
148.6, 83.5, 54.7, 53.4, 25.6.
6
): δ (ppm) 172.3, 170.7, 159.2,
MHz, CDCl
3
+
Triethyl isoxazole-3,4,5-tricarboxylate (7a).79 Yellow oil; 154
mg (45%), R = 0.42 (20% Ethylacetate : n-Hexane); FT-IR
(neat): υ = 1741, 1735, 1732 cm ; H NMR (500 MHz, CDCl
calcd. for C12
10 2 3
H N O (M+H) : 231.0770.
f
5-(Hydroxymethyl)-isoxazol-3-yl)(phenyl)methanone (3x).75
-1
1
):
δ (ppm) 4.49-4.42 (m, 6H), 1.44-1.38 (m, 9H); C{ H} NMR
(125 MHz, CDCl ): δ (ppm) 159.8, 159.1, 157.9, 155.2, 154.3,
117.9, 63.2, 63.0, 62.8, 13.97, 13.95, 13.93.
(
3
1
3
1
Pale yellow oil; 145mg (68%), R = 0.34 (20% Ethylacetate : n-
Hexane); FT-IR (neat): υ = 3425, 1662, 1593 cm ; H NMR
500 MHz, CDCl ): δ (ppm) 8.27 (dd, J = 8.5, 1.5 Hz, 2H), 7.67-
.63 (m, 1H), 7.52 (t, J = 8.0 Hz, 2H), 6.78 (s, 1H), 4.86 (s, 2H),
f
-1 1
3
(
3
7
2
1
13
1
79
.68 (br-s, 1H); C{ H} NMR (125 MHz, CDCl
3
): δ (ppm)
4,5-Diethyl 3-methyl isoxazole-3,4,5-tricarboxylate (7b). Yel-
low oil; 160 mg (49%), R = 0.41 (20% Ethylacetate : n-Hex-
ane); FT-IR (neat): υ = 1741, 1736, 1731 cm ; H NMR (500
MHz, CDCl ): δ (ppm) 4.49-4.43 (m, 4H), 4.01 (s, 3H), 1.43-
85.8, 172.3, 161.8, 135.6, 134.2, 130.7, 128.6, 102.9, 56.4.
f
-1 1
(5-(1-Hydroxycyclohexyl)isoxazol-3-yl)(phenyl)methanone
3
7
2
13
1
(
3y). Pale yellow oil; 185 mg (84%), R
f
= 0.56 (20%
3
1.38 (m, 6H); C{ H} NMR (125 MHz, CDCl ): δ (ppm) 159.7,
Ethylacetate : n-Hexane); FT-IR (neat): υ = 3517, 2934, 2859,
159.2, 158.4, 155.1, 154.1, 117.9, 63.2, 62.8, 53.5, 13.9.
-
1
1
1
(
2
(
742, 1698 cm ; H NMR (500 MHz, CDCl
dd, J = 8.5, 1.5 Hz, 2H), 7.66-7.63 (m, 1H), 7.52 (t, J = 8.0 Hz,
H), 6.71 (s, 1H), 2.13 (br-s, 1H), 2.03-2.00 (m, 2H), 1.95-1.94
m, 2H), 1.79-1.77 (m, 1H), 1.63-1.59 (m, 2H), 1.41-1.39 (m,
3
): δ (ppm) 8.29
Trimethyl isoxazole-3,4,5-tricarboxylate (7c).79 Yellow solid;
f
170 mg (49%), R = 0.38 (20% Ethylacetate : n-Hexane); Mp
o
-1 1
98-100 C; FT-IR (neat): υ = 1738, 1735, 1731 cm ; H NMR
13
1
13
1
1
H), 1.26-1.25 (m, 1H), 0.99-0.87 (m, 1H); C{ H} NMR (125
): δ (ppm) 185.9, 178.8, 161.7, 135.7, 134.0, 130.7,
28.6, 100.8, 70.4, 36.6, 29.7, 25.1, 21.6, 14.1.
3
(400 MHz, CDCl ): δ (ppm) 4.02 (s, 6H), 3.98 (s, 3H); C{ H}
MHz, CDCl
1
3
NMR (125 MHz, CDCl3): δ (ppm) 160.1, 159.1, 158.4, 155.5,
154.1, 117.8, 53.6, 53.54, 53.52.
Ethyl 5-phenyl-4,5-dihydroisoxazole-3-carboxylate (5a).76
Clear oil; 125 mg (62%), R = 0.31 (20% Ethylacetate : n-Hex-
ane); FT-IR (neat): υ = 1718, 1592 cm ; H NMR (500 MHz,
CDCl ): δ (ppm) 7.39-7.32 (m, 5H), 5.78 (dd, J = 11.5 and 9.0
73
3,4-Bis(ethoxycarbonyl)-1,2,5-oxadiazole 2-oxide (3a′). Yel-
-1 1
low oil; FT-IR (neat): υ = 2987, 1748, 1626 cm ; H NMR (500
MHz, CDCl ): δ (ppm) 4.43 (q, J = 7.0 Hz, 2H), 4.38 (q, J = 7.0
Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H);
f
-1 1
3
3
1
3
1
Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 3.64 (dd, J = 18.0 and 11.5
Hz, 1H), 3.22 (dd, J = 18.0 and 9.0 Hz, 1H), 1.38 (t, J = 7.0 Hz,
C{ H} NMR (125 MHz, CDCl
3
): δ (ppm) 156.7, 155.1, 148.4,
106.8, 63.7, 13.94, 13.90.
13
1
3
1
H); C{ H} NMR (125 MHz, CDCl
3
): δ (ppm) 160.6, 151.2,
39.5, 128.9, 128.7, 125.9, 84.9, 62.2, 41.5, 14.1.
ASSOCIATED CONTENT
Supporting Information
8
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Page 9 of 11
The Journal of Organic Chemistry
selective aerobic oxidation of amines into imines. Catal.
The Supporting Information is available free of charge on the ACS
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Publications website at DOI: H NMR, C{ H}NMR spectra of
3a-y, 5a-e and 7a-c; X-Ray analysis of 3k; CIF file of 3k.
Sci. Technol. 2018, 8, 3910-3917.
9
)
Li, C. J. Organic Reactions in Aqueous Media with a Fo-
cus on Carbon−Carbon Bond Formations: A Decade Up-
date. Chem. Rev. 2005, 105, 3095-3165.
AUTHOR INFORMATION
Corresponding Author
1
0) Breslow, R. Hydrophobic Effects on Simple Organic Re-
actions in Water. Acc. Chem. Res. 1991, 24, 159-164.
11) Li, C. J. Organic Reactions in Aqueous Media-With a Fo-
*
E-mail:
karthiclri@gmail.com
and
chandra-
cus on Carbon-Carbon Bond Formation. Chem. Rev.
sekar.praveen@gmail.com
1
993, 93, 2023-2035.
1
1
2) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L. Re-
ORCID
cent Advances in Lewis Acid Catalyzed Diels−Alder Re-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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5
6
7
8
9
0
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2
3
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5
6
7
8
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0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
actions in Aqueous Media. Eur. J. Org. Chem. 2001
439–455.
,
K. Karthikeyan: 0000-0001-5348-8810
3) Dandia, A.; Arya, K.; Sati, M.; Sarawgi, P. Green Chem-
ical Synthesis of Fluorinated 1,3,5-Triaryl-s-Triazines in
Aqueous Medium under Microwaves as Potential Anti-
fungal Agents. J. Fluorine Chem. 2004, 125, 1273–1277.
Chandrasekar Praveen: 0000-0001-6999-6801
Notes
The authors declare no competing financial interest.
14) Wang, X. -S.; Zhang, M. -M.; Zeng, Z. -S.; Shi, D. -Q.;
Tu, S. -J.; Wei, X. -Y.; Zong, Z. -M. A Simple and Clean
Procedure for the Synthesis of Polyhydroacridine and
Quinoline Derivatives: Reaction of Schiff Base with 1,3-
Dicarbonyl Compounds in Aqueous Medium. Tetrahe-
dron Lett. 2005, 46, 7169–7173.
ACKNOWLEDGMENT
This work was financially supported by the Science and Engineer-
ing Research Board (SERB), India under the fast track scheme to
authors
K.
K.
(SB/FT/CS-033/2013)
and
C.
P.
(SERB/F/5666/2015-16) respectively. M. V. likes to thank Council
of Scientific and Industrial Research (CSIR), New Delhi for
providing Senior Research Fellowship (SRF). C. P. acknowledges
Dr. N. Kalaiselvi, Director, CSIR-CECRI for her constant encour-
agement and support. Department of Science and Technology
1
5) Cho, C. S.; Kim, J. S.; Oh, B. H.; Kim, T. -J.; Shim, S.
C.; Yoon, N. S. Ruthenium-Catalyzed Synthesis of Quin-
olines from Anilines and Allylammonium Chlorides in an
Aqueous Medium via Amine Exchange Reaction. Tetra-
hedron 2000, 56, 7747–7750.
(DST) is greatly acknowledged for providing INSPIRE faculty
16) Khadilkar, B. M.; Gaikar, V. G.; Chitnavis, A. A. Aque-
ous Hydrotrope Solution as a Safer Medium for Micro-
wave Enhanced Hantzsch Dihydropyridine Ester Synthe-
sis. Tetrahedron Lett. 1995, 36, 8083–8086.
17) Cho, C. S.; Kim, J. H.; Shim, S. C. Ruthenium-Catalyzed
Synthesis of Indoles from Anilines and Trialkanolammo-
nium Chlorides in an Aqueous Medium. Tetrahedron
Lett. 2000, 41, 1811–1814.
award and research grant (IFA-14/MS-27) to C. P. The authors
would like to thank the Department of Chemistry, Indian Institute
of Technology-Madras (IITM), India for single crystal X-ray dif-
fraction and high-resolution mass spectrometric analysis.
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