Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5-Disubstituted Isoxazoles

Article abstract of DOI:10.1002/jhet.2065

An efficient procedure for the synthesis of 3,5-disubstituted isoxazoles via [3+2] cycloaddition reaction of in situ generated nitrile oxides with acetylenes employing readily preparable copper(0) nanoparticles is described. A variety of in situ generated

Full text of DOI:10.1002/jhet.2065

Month 2014
Copper(0) Nanoparticles in Click Chemistry: Synthesis of
3,5-Disubstituted Isoxazoles
*
T. M. Vishwanatha and Vommina V. Sureshbabu
# 109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar
Veedhi, Bangalore University, Bangalore 560 001, India
*
E-mail: sureshbabuvommina@rediffmail.com
Additional Supporting Information may be found in the online version of this article.
Received March 4, 2013
DOI 10.1002/jhet.2065
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An efficient procedure for the synthesis of 3,5-disubstituted isoxazoles via [3 + 2] cycloaddition reaction
of in situ generated nitrile oxides with acetylenes employing readily preparable copper(0) nanoparticles is
described. A variety of in situ generated nitrile oxide and acetylenic substrates were engaged in the study
and found to undergo cyclization in short duration affording respective isoxazoles in excellent yield. Several
amino acid-derived isoxazoles were also prepared in high yield. Consistent activity of the recovered catalyst
was found to be almost same up to three cycles.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
low yields, and are generally incompatible with the
sensitive functional groups. Several of such inadequacies
were effectively addressed by the Cu-catalyzed
cycloaddition between nitrile oxide and terminal acetylene
[11]. Micoulin group described AlCl3 as an efficient
catalyst for the regioselective synthesis of 3,5-disubstituted
isoxazoles [12]. Additionally, regioselective cycloaddition
of nitrile oxides with acetylenes was also carried out in
presence of (Bu3Sn)2O through in situ generation of nitrile
oxides [13].
In recent years, metal nanoparticles catalysis has
conceived as a valuable protocol in contemporary organic
synthesis, providing both economic and environmental
benefits [14]. The high surface-to-volume ratio of metal
nanoparticles enhances the reaction rate, and catalyst can
be reused without loss of its activity [15]. The synthesis
and application of copper(0) nanoparticles (CuNPs) [either
Cu(0), Cu(I), or Cu(II) NPs] has attracted special interest in
organic reactions [16]. Recent investigations have revealed
that copper catalysts can also promote Pd-catalyzed
reactions as well [17]. Among all copper catalyzed
reactions, a distinguishable and systematic investigation
is being focused for the Cu(I)-catalyzed azide-alkyne
cycloaddition reaction with respect to increase in the
overall efficiency of the reaction [18]. Thus, it has been
demonstrated that the use of catalytic amount of Cu has
Current trends in drug discovery have witnessed a
tremendous growth in the development of heterocycle
tethered target molecules [1]. Owing to their interesting
biological properties, the dipolar cycloaddition chemistry
has facilitated the assembly of biologically significant
molecules [2]. Thus, the copper-catalyzed click concept
(CuAAC) introduced independently by Meldal [3] and
Sharpless [4] groups is an amenable methodology for
regioselective preparation of triazoles and isoxazoles. The
Cu(I)-catalyzed [3 + 2] cycloaddition reaction provides
selectively 1,4-disubstituted-1,2,3-triazole and 3,5-
disubstituted isoxazole when the terminal alkyne is
reacted with an alkyl azide or a nitrile oxide, respectively
[5]. Several 3,5-disubstituted isoxazole-bearing molecules
are categorized to be biologically and pharmaceutically
important and have found to exhibit analgesic,
anti-inflammatory, and hypoglycemic properties [6]. The
isoxazoles prevail in many natural products such as
muscimol and ibotenic acid [7].
Some of the traditional methods for the synthesis of 3,5-
disubstituted isoxazoles include nonmetal-catalyzed
reaction of hydroxyl amines with α,β-unsaturated carbonyl
compounds [8], cyclization of β,γ-acetylenic derivatives
[9], and dehydrogenation of isoxazolines [10]. Most of
these methods often result in mixture of regioisomers,
© 2014 HeteroCorporation

T. M. Vishwanatha and V. V. Sureshbabu
Vol 000
made a wide impact in the yield and reaction profile [19].
Consequently, broad array of both homogenous [20] and
heterogeneous catalytic [21] systems has been explored
for the synthesis of 1,4-disubstituted 1,2,3-triazoles.
However, the reaction conditions and yields of the
products drastically vary to one another. Besides these
efforts, another feasibility to expand the domain of catalyst
for click reaction is to explore copper catalyst in nanoscale
[22]. Interestingly, a series of contributions were disclosed
for azide-alkyne cycloaddition using CuNPs [either Cu(0),
Cu(I), or Cu(II)] [23–33]. It proved possible to obtain the
triazole products using CuNPs in short duration with good
yields and complete regioselectivity. Additionally, by the
use of CuNPs, a series of advantages can be encountered,
in particular, minimization of catalyst loading, reusability,
and operational simplicity [34]. Recently, Alonso group
demonstrated that CuNPs were found to speed up the
one-pot click reaction from epoxide ring opening with
azides followed by click ligation [35]. Another major
finding made was Cu(0) can also be used as catalytic
species in the regioselective synthesis of 1,4-disubstituted
1,2,3-triazoles [34]. These major discoveries on CuNPs
catalyzed azide-alkyne cycloaddition would reflect the
flowering of contemporary CuAAC click chemistry to
enlarge growing menu of products. Although both 1,4-
reports describing the application of Cu(0)NPs for 3,5-
disubstituted isoxazoles synthesis.
RESULTS AND DISCUSSION
Preparation and characterization of catalyst.
CuNPs
were prepared by reducing copper sulfate (CuSO4·5H2O)
with sodium borohydride (NaBH4) in acetonitrile (ACN)
(Scheme 1) [36]. The resulting black powder can be
stored under inert atmosphere for several days. The
CuNPs were characterized by several techniques
including ICP-OES, XRD, UV–vis, XPS, SEM, and
TEM analyses.
Initially, complete reduction of Cu(II) to Cu(0) was
confirmed by ICP-OES analysis of the CuNPs [presence of
99.7% Cu(0) content]. The powder XRD pattern of CuNPs
revealed that the peak positions are consistent with the me-
tallic copper (Fig. 1(a)). UV–vis absorption spectrum of
CuNPs shows band around 579nm, which is in good agree-
ment with the reported values of CuNPs (Fig. 1(b)).
TEM analysis of the CuNPs showed that copper powder
is constituted by small particles, and they are aggregated as
spongy ensembles smaller than 20 nm (Fig. 2(a)). The
metallic copper has also been confirmed by selected area
electron diffraction pattern of CuNPs (Fig. 2(b)).
The X-ray photoelectron spectrum of CuNPs showed a
single peak at 932.8 eV, which corresponds to the binding
energy of Cu2P3/2. Additionally, CuNPs are graphically
observed by using SEM. On the basis of SEM images,
the CuNPs are estimated to be around 0.2 μm in size
(Fig. 3).
disubstituted
1,2,3-triazoles
and
3,5-disubstituted
isoxazoles are the CuAAC click products, no studies have
been carried out pertaining to the later one employing
CuNPs. In this regard, we herein demonstrate the emerging
versatility and catalytic activity of CuNPs in the 1,3-
dipolar cycloaddition of in situ generated nitrile oxide with
acetylene. To the best of our knowledge, there are no
Synthesis
CuNPs.
of
3,5-disubstituted
isoxazoles
using
Our objective was to capitalize the catalytic
activity of CuNPs for [3 + 2] cycloaddition reaction between
in situ generated nitrile oxide and terminal acetylene.
Imidoyl chlorides 1 are the masked precursors for nitrile
oxides and were prepared from the corresponding aldoximes
by oxidative halogenations [37]. In an initial experiment, 4-
Scheme 1. Preparation of CuNPs.
Figure 1. (a) The XRD pattern of CuNPs and (b) UV–vis absorption spectra of CuNPs in ethanol.
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Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5-Disubstituted Isoxazoles
Figure 2. (a) Transmission electron micrograph (TEM) of CuNPs (bar length = 20 nm). (b) Selected electron diffraction (SEAD) pattern of CuNPs.
Figure 3. (a) XPS spectrum of Cu2p region for CuNPs. (b) SEM image of CuNPs.
chloro-N-hydroxybenzimidoyl chloride 1a and propiolic acid
2a were used as model substrates (Scheme 2) to study the
catalytic activity of CuNPs in various solvents (Table 1).
The reaction was carried out by employing 5 mol% of
CuNPs and TEA (2.0 equiv) in ACN at room temperature.
To our delight, it afforded 3a in 98% yield (Table 1, entry
9). Effective product formation was observed with polar
aprotic solvents as well (Table 1, entries 6–11). It has been
observed that DMF and DMSO also gave good result.
However, ACN was the preferred solvent because of the
ease of isolation of product. Efficacy of CuNPs was
compared with bulk Cu catalysts such as CuSO4·5H2O, CuI,
Cu powder, and Cu(OAc)2·2H2O in the presence of
additives (Table 1, entries 1–5). Either at room temperature
or at reflux condition, the yield was not satisfactory when
bulk Cu sources were employed as catalyst. Cycloaddition
of 1a with 2a was conducted without copper source also. It
leads to a moderate yield of 3a along with its regioisomer
(Table 1, entry 15). Thus, it has been confirmed that CuNPs
provided the best conversion, and therefore, we then
conducted the study of this catalyst loading. When the
amount of CuNPs was increased from 2 to 5 mol%, the
yield of the product 3a was raised considerably from 84% to
98%, and the duration of reaction reduced from an hour to
25 min (Table 1, entries 9 and 12). Furthermore, increase in
the amount of CuNPs up to 15 mol% did neither improve
the yield nor reduce the reaction duration considerably
(Table 1, entries 13 and 14).
To study the scope of the optimized protocol, a series of
imidoyl chlorides were cyclized with various terminal
acetylenes (Scheme 2, Table 2). The product formation
was found to be complete within 30 min at RT and was
easily isolated by a simple work-up. The crude products
were purified through recrystallization using MeOH:H2O.
The structural assignment was made by mass spectrometry,
1H NMR, and 13C NMR analyses and was further
confirmed by comparing with literature data.
Scheme 2. Synthesis of 3,5-disubstituted isoxazoles mediated by CuNPs.
The present methodology was further explored to
introduce isoxazole ring into the amino acid derivatives 6
(Scheme 3). For this, amino acid aldoximes 4 were
prepared via treatment of N-protected aminals [38] with
hydroxylamine [39]. These precursors were then converted
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T. M. Vishwanatha and V. V. Sureshbabu
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Table 1
Optimization of the click chemistry protocol for the synthesis of 3a using various Cu sources.
Entry
Catalyst (mol%)
Additive
NaAsc
Solvent
Temp (°C)
Time
Yield (%)
1
2
3
4
5
6
7
8
CuSO4·5H2O (20)
Cu powder (20)c
Cu(OAc)2·3H2O (18)
CuI (15)
CuSO4·5H2O (15)
CuNPs (5)
CuNPs (5)
CuNPs (5)
CuNPs (5)
CuNPs (5)
CuNPs (5)
CuNPs (2)
CuNPs (10)
CuNPs (15)
None
tBuOH:H2O
THF
35
65
RT
70
6 h
5 h
7 h
5 h
4 h
55 min
1.5 h
1.5 h
25 min
32 min
30 min
1 h
35 min
40 min
15 h
55a
39a
61a
70a
71a
61b
77b
79b
98b
96a
96a
84b
96b
95a
63a,d
TEA
NaAsc
TEA
NaAsc
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
tBuOH:H2O
ACN
ACN
THF
Toluene
1,4-Dioxane
ACN
DMF
DMSO
ACN
ACN
ACN
65
RT
RT
30
RT
55
RT
RT
RT
RT
RT
9
10
11
12
13
14
15
ACN
aIsolated yield after column chromatography.
bIsolated yield after recrystallization in MeOH:H2O.
cCu-powder (1–5 μm).
dYield refers to both regioisomers as observed by 1H NMR.
to reactive imidoyl intermediates by treatment with N-
chlorosuccinimide and cyclized in situ with acetylenic
substrates through the present protocol (see Experimental
section). The amino acid derived imidoyl chlorides showed
less stability to isolation and hence were put to use imme-
diately after their generation in a one-pot protocol. Practi-
cally, in all the cases, the reactions were neat, and yields
were excellent (Table 3). A few isoxazole tethered orthog-
onally protected dipeptide mimetics were also prepared in
good yield. These results confirm that CuNPs can also be
used for one-pot synthesis of isoxazoles from aldoximes.
The solution affords product 3q after evaporation of the
solvent followed by recrystallization. By using the
recovered CuNPs (98%), the next three cycles were
performed with the same substrates under the similar
reaction conditions. It is noteworthy to mention that no
drastic decrease in the product yield was observed at the
end of the fourth cycle. However, XRD analysis of each
cycle reveals the presence of CuO (Fig. 5).
A
considerable amount of CuO was observed after fourth
cycle. This might be due to frequent air and moisture
exposure during the study.
Recyclability of the catalyst. ACN is also known to be
useful as protecting agent during the preparation of
CuNPs [34]. Thus, the recyclability of the CuNPs was
tested using ACN as solvent. Cycloaddition experiment
using CuNPs was performed for the reaction of
pentafluoro N-hydroxyimidoyl chloride 1q with propargyl
alcohol 2c as indicated in Figure 4. The reaction medium
was appeared partially homogeneous. The solubility of
CuNPs is perhaps due to the presence of NEt3HCl in the
reaction mixture. To recover the CuNPs, after completion
of the reaction, the volume of the solution was
evaporated to half of its volume and was then diluted
with distilled H2O and stirred for 5 min. The CuNPs were
settled slowly, and the supernatant solution was decanted
followed by subsequent washings with ACN (Fig. 4).
CONCLUSION
In conclusion, inexpensive and easily preparable CuNPs
has been shown to be an active and versatile catalyst for the
synthesis of 3,5-disubstituted isoxazoles. Cu(0)NPs have
been first time successfully used for regioselective
cycloaddition of nitrile oxides with acetylenes under click
chemistry concept. The employed protocol is mild, has
short duration of reaction, high yielding, and reproducible.
A variety of aromatic as well as aliphatic substrates
including optically pure amino acid-derived ones were
employed in the study, and corresponding isoxazoles were
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Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5-Disubstituted Isoxazoles
Table 2
List of 3,5-disubstituted isoxazoles prepared.
Entry
a
R1
R2
Product 3
Yielda (%)
98
Timeb (min)
25
b
c
96
98
30
20
d
e
97
96
25
20
f
97
20
g
h
94
89
25
30
i
93
96
25
20
J
k
l
97
99
20
30
(Continued)
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T. M. Vishwanatha and V. V. Sureshbabu
Vol 000
Table 2
(Continued)
Entry
m
R1
R2
Product 3
Yielda (%)
97
Timeb (min)
25
n
98
25
o
p
97
95
25
30
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), TEA (2.0 mmol), and CuNPs (5 mol%) were stirred at RT in ACN (5.0 mL) under nitrogen atmosphere.
aYields of the recrystallized products.
bTime refers to the complete consumption of acetylene 2.
General procedure for the preparation of 3,5-disubstituted
Scheme 3. Synthesis of isoxazole tethered amino acids/ peptides.
isoxazoles 3. CuNPs (5 mol%) was added to a clean 10-mL flask
containing ACN (1–2 mL). While the solution was stirred under
argon, TEA (2.1 mmol), alkyne 2 (1.1 mmol), and imidoyl chloride
1 (1.1 mmol) were added. The flask was stirred at room temperature
for 20–30 min, and the reaction progress was monitored by TLC
analysis (complete consumption of alkyne). After completion of the
reaction, volatiles were removed under vacuo, and the residue was
isolated. In addition, consistent catalytic activity has been
observed by recycling of the catalyst up to three times.
extracted with EtOAc (10 mL). The extract was washed with water
and brine and dried over anhydrous Na2SO4. The crude product
was purified by recrystallization in MeOH:H2O (5:0.8 mL/800 mg)
system afford pure 3,5-disubstituted isoxazole derivatives.
General procedure for the preparation of N-protected
EXPERIMENTAL
amino acid aldoximes 4.
A solution of N-protected amino
aldehyde (5.0 mmol) in MeOH:H2O (1:1 v/v, 100 mL) was cooled to
0°C. To this solution, TEA (5.1 mmol) and NH2OH·HCl (10.0 mmol)
were added. After completion of the reaction (TLC analysis), the
solvent was evaporated in vacuo to a half of the original volumes.
The mixture was extracted with EtOAc and washed with brine, dried
over MgSO4, filtered and concentrated in vacuo and affords
respective oximes and were purified through column chromatography.
General information. TEM analyses were performed on CM
200 instrument operating at 20–200 kV with a resolution at 2.4 Å.
XRD studies were carried out on D8 advance diffractometer
(λ = 1.5405 Å). SEM measurements were made on a 5600LV
electron microscope. Melting points were determined in open
1
capillary tubes in a circulating oil melting point apparatus. H and
13C NMR spectra were recorded in CDCl3 solution with Me4Si as
an internal standard. High resolution mass spectra were obtained on
an (HRMS) Q-Tof micro mass spectrometer. All reagents and
solvents were used as supplied.
General procedure for the preparation of amino acid
derived isoxazoles 6.
To a solution of N-chlorosuccinimide
(2.5 mmol) and TEA (2.2 mmol) in ACN (5 mL) was added N-
protected amino acid aldoximes (1.0 mmol) at 0°C. The imidoyl
chloride generated in situ was confirmed through TLC analysis
(usually 30–45 min). The reaction mixture was then allowed to
reach RT; CuNPs (5 mol%) and acetylene (1.1 mmol) were added.
The product formation was monitored through TLC analysis. A
simple work-up followed by recrystallization with THF:n-pentane
(1:3.5 mL/1 g) gave pure products.
Typical procedure for the preparation of Cu(0)NPs
[34].
CuSO4·5H2O (600 mg, 2.4 mmol) was dissolved in a
mixture of CH3CN (70 mL) and deionized water (30 mL). Argon was
bubbled to the reaction medium; a freshly prepared NaBH4 solution
(100 mg in 2 mL H2O, 2.6 mmol) was added drop by drop via
syringe pump. The addition of the sodium borohydride solution was
continued till the reaction mixture turned wine reddish. After
the reduction was complete, the solution was centrifuged;
separated copper particles were washed with methanol and
dried in vacuum.
3-(4-Chlorophenyl) isoxazole-5-carboxylic acid (3a)
[11b].
Yield=98%, white solid, mp 183–184°C; 1H NMR
(CDCl3, 300 MHz) δ (ppm) 9.22 (s, 1H), 7.41 (d, 2H, J=6.2Hz),
7.33 (d, 2H, J= 3.4 Hz), 6.99 (s, 1H); 13C NMR (CDCl3, 75MHz)
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Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5-Disubstituted Isoxazoles
Table 3
List of amino-derived isoxazoles 6.
Entry
a
Aldoximes 4
Acetylenes 5
Product 6
Yielda
88
Time (min)b
30
b
c
92
94
30
25
d
e
96
93
30
20
f
89
95
86
25
25
30
g
h
i
96
25
aYields are given with respect to 5.
bTime given for cycloaddition duration after in situ generation of chloroximes.
Figure 4. Recycling experiment of CuNPs.
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T. M. Vishwanatha and V. V. Sureshbabu
Vol 000
Figure 5. XRD patterns of recovered CuNPs (a) first cycle, (b) second cycle, (c) third cycle, and (d) fourth cycle. TEM image of recovered CuNPs after
third cycle (right, bar length = 20 nm).
δ (ppm) 173.3, 162.9, 155.1, 133.7, 129.5, 128.5, 128.3, 128.1, 99.2;
HRMS Calcd for C10H6ClNO3 m/z 245.9934 [M + Na]+; found
245.9901.
5 - (4 - Methoxybenzyl) -3 - (4 - ethoxyphenyl)isoxazole (3h).
Yield=89%, white solid, mp 75–77°C; 1H NMR (CDCl3,
300 MHz) δ (ppm) 7.29 (d, 2H, J= 5.8 Hz), 6.91 (s, 1H), 6.77 (d,
2H, J= 7.0 Hz), 6.58 (s, 4H), 5.14 (s, 2H), 3.78–3.85 (m, 2H), 3.48
(s, 3H), 1.11 (t, 3H, J=6.6Hz); 13C NMR (CDCl3, 75MHz) δ
(ppm) 162.0, 157.8, 156.0, 152.1, 127.3, 122.3, 113.8, 113.6,
113.5, 113.3, 112.6, 98.0, 64.6, 61.9, 54.9, 11.5; HRMS Calcd for
C19H19NO4 m/z 348.1212 [M + Na]+; found 348.1204.
3,5-Diphenylisoxazole (3b)[11a]. Yield = 96%, white solid,
1
mp 61–62°C; H NMR (CDCl3, 300 MHz) δ (ppm) 7.86 (d, 2H,
J= 3.8 Hz), 7.67 (d, 2H, J= 1.9 Hz), 7.22–7.41 (m, 6H), 6.78 (s,
1H); 13C NMR (CDCl3, 75MHz) δ (ppm) 168.8, 160.5, 132.9,
130.0, 129.3, 127.5, 125.5, 97.2; HRMS Calcd for C15H11NO m/z
244.0738 [M + Na]+; found 244.0700.
Methyl 3-(4-bromophenyl) isoxazole-5-carboxylate . (3c)
Yield=98%, white solid, mp 131–133°C; 1H NMR (CDCl3,
300 MHz) δ (ppm) 7.36 (d, 2H, J= 6.8 Hz), 7.22 (d, 2H,
J= 3.9 Hz), 6.81 (s, 1H), 3.77 (s, 3H); 13C NMR (CDCl3, 75MHz)
δ (ppm) 168.8, 162.0, 156.6, 132.9, 129.0, 128.7, 128.4, 128.3,
123.0, 98.7, 50.1; HRMS Calcd for C11H8BrNO3 m/z 303.9
[M + H]+ 281.9765; found 281.9683.
3-tert-Butyl-5-[(4-methoxyphenoxy)methyl] isoxazole (3d)
[11a]. Yield=97%, white solid, mp 53–55°C; 1H NMR (CDCl3,
300 MHz) δ (ppm) 7.38 (s, 4H), 6.86 (s, 1H), 5.18 (s, 2H), 3.51 (s,
3H), 1.28 (s, 9H); 13C NMR (CDCl3, 75MHz) δ (ppm) 156.9,
151.8, 148.8, 113.0, 99.6, 62.2, 52.7, 37.6, 29.9; HRMS Calcd for
C15H19NO3 m/z 284.1263 [M + Na]+; found 284.1251.
3-Pentylisoxazole-5-carboxylic acid (3i).
Yield = 93%,
white solid, mp 120–121°C; 1H NMR (CDCl3, 300 MHz) δ
(ppm) 10.55 (s, 1H), 6.90 (s, 1H), 2.40 (t, 2H, J = 5.6 Hz), 1.42–
1.61 (m, 2H), 1.11–1.19 (m, 4H), 0.86 (t, 3H, J = 7.1 Hz); 13C
NMR (CDCl3, 75 MHz) δ (ppm) 170.9, 156.8, 147.8, 98.7,
30.6, 30.0, 29.6, 20.9, 13.1; HRMS Calcd for C9H13NO3 m/z
184.0973 [M+ + H]; found 184.0940.
3-(6-Fluoro-4-methylnaphthalen-2-yl)-5-phenylisoxazole. (3j)
Yield = 96%, white solid, mp 98–99°C; 1H NMR (CDCl3, 300 MHz)
δ (ppm) 7.62 (d, 1H, J= 5.4 Hz), 7.34 (d, 1H, J= 5.9 Hz), 7.25–7.30
(m, 6H), 7.01 (d, 1H, J=4.6Hz), 6.87 (s, 1H), 2.55 (s, 3H); 13C NMR
(CDCl3, 75MHz) δ (ppm) 167.7, 160.9, 156.0, 132.7, 131.9, 129.7,
128.3, 127.6, 125.6, 124.9, 113.8, 105.7, 97.3, 21.0; HRMS Calcd for
C20H14FNO m/z 326.0957 [M + Na]+; found 326.0909.
3-Cyclohexynylisoxazole-5-carboxylic acid (.3e) Yield=96%,
white solid, mp 49–51°C; H NMR (CDCl3, 300 MHz) δ (ppm)
10.11 (s, 1H), 6.91 (s, 1H), 5.74 (t, 1H, J=5.6Hz), 1.65–1.79 (m,
4H), 1.41–144 (m, 4H); 13C NMR (CDCl3, 75MHz) δ (ppm)
173.3, 168.6, 156.1, 141.8, 122.2, 98.8, 29.7, 26.1, 25.5, 21.6;
HRMS Calcd for C10H11NO3 m/z 216.0637 [M + Na]+; found
216.0613.
1-{4-[(3-(Thiophen-2-yl)isoxazol-5-yl)methoxy]phenyl}ethanone
(3k). Yield = 97%, white solid, mp 132–134°C; 1H NMR (CDCl3,
300 MHz) δ (ppm) 7.63 (d, 2H, J=7.0Hz), 7.06–7.15 (m, 3H), 6.89
(s, 1H), 6.78 (d, 2H, J= 6.8 Hz), 5.11 (s, 2H), 2.13 (s, 3H); 13C
NMR (CDCl3, 75MHz) δ (ppm) 198.5, 163.3, 156.0, 148.3, 138.8,
128.2, 127.5, 125.6, 120.5, 112.5, 97.1, 62.7, 25.2; HRMS Calcd for
C16H13NO3S m/z 322.0514 [M + Na]+; found 322.0507
1
[3-(Pentafluorophenyl) isoxazol-5-yl]methanol (3f)[11a].
Yield = 97%, white solid, mp 141–143°C; 1H NMR (CDCl3,
300 MHz) δ (ppm) 5.89 (s, 1H), 4.55 (s, 2H), 1.90 (br, s, 1H);
13C NMR (CDCl3, 75 MHz) δ (ppm) 160.9, 156.5, 144.2,
141.8, 136.0, 109.5, 98.1, 55.0; HRMS Calcd for C10H4F5NO2
m/z 266.0240 [M + H]+; found 266.0237.
[3-(4-Nitrophenyl)isoxazol-5-yl]methanol (3l)[11b]. Yield = 99%,
white solid, mp 116–117°C; H NMR (CDCl3, 300 MHz) δ (ppm)
8.08 (d, 2H, J= 5.8 Hz), 7.61 (d, 2H, J= 6.5 Hz), 6.90 (s, 1H), 4.52
(s, 2H), 1.91 (br, s, 1H); 13C NMR (CDCl3, 75MHz) δ (ppm)
161.0, 155.4, 145.0, 137.0, 128.7, 128.6, 120.1, 97.0, 55.1; ESI-MS
Calcd for C10H9N2O4 m/z 221.0 [M+ + H]; found 221.0.
1
(3-Isobutylisoxazol-5-yl)methanamine (3g). Yield = 94%,
colorless oil; H NMR (CDCl3, 300 MHz) δ (ppm) 6.91 (s, 1H),
3.76 (s, 2H), 2.51 (m, 2H), 2.09–2.29 (m, 1H), 1.81 (br, s, 2H), 0.96
(d, 3H, J= 7.1 Hz), 0.81 (d, 3H, J=6.8Hz); 13C NMR (CDCl3,
75 MHz) δ (ppm) 156.1, 148.8, 98.1, 41.3, 36.8, 26.1, 22.6, 22.5;
ESI-MS Calcd for C8H14N2O m/z 155.1 [M+ + H]; found 155.1.
3-Phenylisoxazole-5-carboxylic acid (3m)[11b]. Yield = 97%,
1
1
white solid, mp 176–177°C; H NMR (CDCl3, 300 MHz) δ (ppm)
10.10 (s, 1H), 7.25–7.40 (m, 5H), 6.92 (s, 1H); 13C NMR (CDCl3,
75 MHz) δ (ppm) 174.8, 160.0, 156.1, 132.0, 129.0, 128.9, 128.7,
128.6, 98.0; HRMS Calcd for C10H7NO3 m/z 212.0324 [M + Na]+;
found 212.0300.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Copper(0) Nanoparticles in Click Chemistry: Synthesis of 3,5-Disubstituted Isoxazoles
3-Phenyl-5-hydroxymethylisoxazole (3n)[11b].
Yield = 98%,
J= 11.2 Hz, 2H), 7.15–7.39 (m, 4H), 7.05 (s, 1H), 6.04 (s, br, 1H),
5.29 (s, br, 1H), 4.94 (m, 1H), 4.31 (d, J= 3.8Hz, 2H), 4.19 (t,
J= 5.8 Hz), 3.81 (s, 2H), 1.51 (d, J= 2.9 Hz, 3H), 1.15 (s, 9H); 13C
NMR (CDCl3, 75MHz) δ (ppm) 159.3, 156.7, 156.0, 149.9, 141.5,
140.2, 128.5, 128.3, 128.2, 128.1, 100.0, 80.0, 67.3, 50.9, 45.2,
36.1, 28.5, 20.1; HRMS Calcd for C26H29N3O5 m/z 464.2185
[M + H]+; found 464.2174.
1
white solid, mp 51–53°C; H NMR (CDCl3, 300 MHz) δ (ppm)
7.30 (d, 2H, J= 6.1 Hz), 7.01–7.09 (m, 3H), 6.92 (s, 1H), 4.55 (s,
2H), 2.18 (s, br, 1H); 13C NMR (CDCl3, 75MHz) δ (ppm) 160.9,
157.6, 132.4, 129.6, 129.2, 128.6, 123.7, 100.1, 55.6. HRMS Calcd
for C10H9NO2 m/z 176.0711 [M + H]+; found 176.0708.
3-(Furan-2-yl)-5-phenylisoxazole (3o). Yield = 97%, white
1
solid, mp 90–92°C; H NMR (CDCl3, 300 MHz) δ (ppm) 7.39 (d,
(S)-Benzyl 1-{5-[(tert-butyloxycarbonyl)methyl]isoxazol-3-yl}
ethylcarbamate (6g). Yield = 95%, pale yellow solid, mp 148–
2H, J= 3.8 Hz), 7.19 (t, 2H, J= 5.2 Hz), 7.15–7.11 (m, 3H), 6.90 (s,
1H), 6.11 (d, 2H, J=0.8Hz); 13C NMR (CDCl3, 75MHz) δ (ppm)
167.7, 158.0, 149.9, 140.8, 137.7, 132.8, 128.1, 126.9, 126.1,
106.3, 103.6, 99.9; HRMS Calcd for C13H9NO2 m/z 212.0711
[M + H]+; found 212.0700.
1
150°C, [α]2D5 À7.4 (c 0.1, CHCl3); H NMR (CDCl3, 300 MHz) δ
(ppm) 7.15–7.45 (m, 5H), 6.89 (s, 1H), 6.35 (s, br, 1H), 5.11 (s,
2H), 4.79 (m, 1H), 3.71 (s, 2H), 1.78 (d, 3H, J= 7.8 Hz), 1.15 (s,
9H); 13C NMR (CDCl3, 75MHz) δ (ppm) 160.3, 157.0, 149.7,
140.1, 129.0, 128.9, 128.7, 128.6, 99.9, 80.2, 67.5, 50.5, 37.6, 28.8,
20.6; HRMS Calcd for C19H25N3O5 m/z 376.1867 [M+ + H]; found
376.1840.
(E)-5-Phenyl-3-styrylisoxazole (3p).
Yield = 95%, white
1
solid, mp 140–141°C; H NMR (CDCl3, 300 MHz) δ (ppm) 7.32
(d, 2H, J= 8.1 Hz), 7.15–7.26 (m, 8H), 7.02 (s, 1H), 6.88 (d, 2H,
J=7.1Hz); 13C NMR (CDCl3, 75MHz) δ (ppm) 168.6, 161.8,
135.8, 132.9, 129.1, 129.0, 128.8, 128.2, 127.6, 125.5, 120.5, 99.8;
HRMS Calcd for C17H13NO m/z 270.0895 [M + Na]+; found
270.0822.
(S)-3-(1-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-2-methylpropyl)
isoxazole-5-carboxylic acid (6h). Yield = 86%, white solid, mp
161–163°C, [α]2D5 À43.3 (c 0.525, MeOH); 1H NMR (CDCl3,
300 MHz) δ (ppm) 10.06 (s, 1H), 7.89 (d, J= 7.9 Hz, 2H), 7.72 (d,
J= 10.8 Hz, 2H), 7.23–7.58 (m, 4H), 6.98 (s, 1H), 6.26 (s, br, 1H),
4.12–4.39 (m, 4H), 1.74 (m, 1H) 0.88 (d, J= 4.8 Hz, 6H); 13C
NMR (CDCl3, 75MHz) δ (ppm) 174.6, 158.2, 156.5, 150.0, 144.2,
141.8, 128.2, 127.5, 125.4, 120.5, 113.0, 99.7, 97.1, 57.0, 47.7,
31.4, 19.9, 18.6; HRMS Calcd for C23H22N2O5 m/z 407.1601
[M+ + H]; found 407.1588.
tert-Butyl (R)-1-(3-((S)-1-{[(9H-fluoren-9-yl)methylthio]carbonyl}-
2-phenylethyl)isoxazol-5-yl)ethylcarbamate (6i). Yield = 96%, white
solid, mp 177–179°C, [α]2D5 À14.6 (c 0.525, MeOH); 1H NMR
(CDCl3, 300MHz) δ (ppm) 7.63 (d, 2H, J= 7.1 Hz), 7.41 (d, 2H,
J= 4.8 Hz), 7.11–7.29 (m, 9H), 6.85 (s, 1H), 5.84 (s, br, 2H), 5.31
(d, 1H, J= 8.1 Hz), 4.90 (m, 1H), 4.44 (d, 2H, J= 3.8 Hz), 4.08 (t,
1H, J= 7.2 Hz), 2.85 (m, 1H), 2.70 (m, 1H), 1.52 (s, 9H), 1.09 (d,
J= 5.6 Hz, 3H); 13C NMR (CDCl3, 75MHz) δ (ppm) 160.0, 155.7,
149.5, 143.8, 141.8, 138.9, 129.1, 129.0, 128.4, 128.3, 128.2,
127.7, 127.6, 125.6, 120.4, 100.0, 80.2, 68.5, 54.0, 50.2, 47.1, 39.6,
36.2, 28.6, 20.0; HRMS Calcd for C33H36N3O5 m/z 554.2649
[M+ + H]; found 554.2611.
(S)-3-[1-(ter-Butoxycarbonyl)ethyl]isoxazole-5-carboxylic acid
(6a). Yield = 88%, white solid, mp 128–130°C, [α]2D5 À21.2
(c 0.525, MeOH); 1H NMR (CDCl3, 300 MHz) δ (ppm) 10.05
(s, 1H), 6.91 (s, 1H), 6.26 (br, s, 1H), 4.65 (m, 1H), 1.29 (s, 9H),
0.97 (d, J=5.1Hz, 3H); 13C NMR (CDCl3, 75MHz) δ (ppm)
174.7, 157.5, 155.0, 148.1, 98.8, 80.2, 48.3, 28.3, 20.4; HRMS
Calcd for C11H16N2O5 m/z [M + Na]+ 279.0957; found 279.0902.
tert-Butyl
[5-(aminomethyl)isoxzol-3-yl]methylcarbamate
1
(6b). Yield = 92%, white solid, mp 95–98°C; H NMR (CDCl3,
300 MHz) δ (ppm) 6.84 (s, 1H), 5.60 (s, br, 1H), 4.09 (s, 2H), 3.69
(s, 2H), 2.11 (s, br, 2H), 1.35 (s, 9H); 13C NMR (CDCl3, 75MHz)
δ (ppm) 158.2, 154.9, 149.2, 99.3, 80.3, 43.8, 40.9, 28.3; HRMS
Calcd for C10H17N3O3 m/z 250.1168 [M + Na]+; found 250.1153.
(S)-Benzyl 3-methyl-1-(5-phenylisoxazol-3-yl)butylcarbamate
(6c).
Yield= 94%, white solid, mp 109–110°C, [α]2D5 À32.7
(c 0.5, CHCl3); 1H NMR (CDCl3, 300 MHz) δ (ppm) 7.38 (d, 2H,
J = 4.6 Hz), 7.19–7.21 (m, 8H), 7.00 (s, 1H), 6.49 (br, s, 1H), 5.02
(s, 2H), 3.89 (t, 1H, J = 5.6 Hz), 1.21–1.34 (m, 3H), 0.92 (d, 6H,
J = 4.7 Hz); 13C NMR (CDCl3, 75MHz) δ (ppm) 168.5, 156.1,
150.1, 140.0, 130.0, 129.0, 128.9, 128.7, 128.6, 127.6, 126.5,
99.0, 67.5, 49.7, 44.7, 23.4, 22.5; HRMS Calcd for C22H24N2O3
m/z 387.1685 [M+ Na]+; found 387.1615.
Acknowledgments. The authors thank the Department of Science
and Technology (Nano mission) for the financial support
(Grant No. SR/NM/NS-13/2007). TMV thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi, for the
award of SRF.
(S)-Benzyl-2-tert-butoxy-1-[5-(hydroxymethyl) isoxazol-3-yl]
ethylcarbamate (6d). Yield=96%, white solid, mp 116–118°C;
[α]2D5 À24.1 (c 0.1, CHCl3), H NMR (CDCl3, 300 MHz) δ (ppm)
1
7.16–7.42 (m, 5H), 6.83 (s, 1H), 6.11 (s, br, 1H), 5.45 (s, 2H), 5.01
(m,1H), 4. 49 (s, 2H), 3.42–3.81 (m, 2H), 2.02 (s, br, 1H), 0.89
(s, 9H); 13C NMR (CDCl3, 75MHz) δ (ppm) 159.1, 155.9, 149.5,
139.7, 131.9, 130.9, 129.0, 128.7, 128.6, 99.1, 75.0, 67.5, 63.9,
54.5, 50.1, 30.1; HRMS Calcd for C18H24N2O5 m/z 371.1583
[M + Na]+; found 371.1531.
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