Synthesis of 1,2,3-triazole substituted isoxazoles via copper (I) catalyzed cycloaddition

Article abstract of DOI:10.1002/jhet.837

The synthesis of a series of 3,5-disubstituted isoxazole-4-carboxylic esters containing N-substituted 1,2,3-triazoles (V) starting from various benzaldehydes (I) is reported. Benzaldehydes undergo oximation with hydroxylamine hydrosulfate. Later, chlorination followed by condensation with methylacetoacetate and the hydrolysis of the resulting ester afforded respective carboxylic acid (II), which on chlorination with PCl₅ gave the corresponding acid chlorides (III). The coraboxylic acid chlorides (III) on propargylation gave propargylic esters (IV) and these on click reaction gave the title compounds (V).

Full text of DOI:10.1002/jhet.837

May 2012
Synthesis of 1,2,3-Triazole Substituted Isoxazoles via Copper (I)
621
Catalyzed Cycloaddition
*
P. Venkata Ramana and A. Ram Reddy
Department of Chemistry, University College of Science, Osmania University,
Hyderabad 500 007, India
*
E-mail: a_ramreddy@yahoo.com
Received September 27, 2010
DOI 10.1002/jhet.837
View this article online at wileyonlinelibrary.com.
The synthesis of a series of 3,5-disubstituted isoxazole-4-carboxylic esters containing N-substituted
1,2,3-triazoles (V) starting from various benzaldehydes (I) is reported. Benzaldehydes undergo oximation
with hydroxylamine hydrosulfate. Later, chlorination followed by condensation with methylacetoacetate
and the hydrolysis of the resulting ester afforded respective carboxylic acid (II), which on chlorination
with PCl5 gave the corresponding acid chlorides (III). The coraboxylic acid chlorides (III) on propargyla-
tion gave propargylic esters (IV) and these on click reaction gave the title compounds (V).
J. Heterocyclic Chem., 49, 621 (2012).
INTRODUCTION
methyl-3-phenylisoxazole-4-carboxylates (Va–d) starting
from benzaldehydes. Zhi-Wei et al. [16] reported the synthesis
of 3-(2-chloro-6-flourophenyl)-5-methylisoxazole-4-carboxylic
acid (IId) from 2-chloro-6-fluoro-benzaldehyde (Id) in
four steps by isolating three respective intermediates.
We have developed a one-pot synthesis of 3-aryl-5-
methylisoxazole-4-carboxylic acid starting from the respec-
tive benzaldehydes with high yield. Benzaldehyde oxime
(Ia2) or substituted benzaldehyde oxime (Ib2–d2) were pre-
pared by oximation of benzaldehyde (Ia1) or substituted
benzaldehyde (Ib1–d1) (1 equiv) with hydroxylamine
hydrosulfate (1.7 equiv) in methanol. The resulting oxime
solution (Ia2–d2) in methanol was treated with Cl2 gas at
0ꢀC to form chloro compound (1a3–d3). Later, to this
mixture was added a methanolic solution of the sodium salt
of methylacetoacetate at 0–5ꢀC to form methyl 5-methyl-3-
phenylisoxazole-4-carboxylates (Ia4–d4). Saponification of
methyl esters (Ia4–d4) by aqueous NaOH (25%) under
reflux condition yielded the key intermediates IIa–d. All
these reactions, i.e., Ia1–d1 to IIa–d, were carried out in a
one-pot experiment without isolating the intermediate mole-
cules by following TLC as depicted in Scheme 1. The forma-
tion of IIa–d was confirmed by a broad singlet for a
carboxylic acid proton in the 1H-NMR spectrum at d
12.52–13.12 (confirmed by exchanging with D2O). In the
13C-NMR spectrum of IIa–d, C-(4) of the isoxazole ring
resonated at up field, between 107.5 and 114.0 ppm and
the carboxyl C-atom gave a peak at around 175 ppm. In com-
pound IId, the fluorine containing ipso-C signal appeared at
d 162.1. The Me group at C-(5) of isoxozole resonated
around 13 ppm in the 13C-NMR spectrum of IIa–d. Mass
Several compounds of natural and non-natural isoxazole
origin possess a broad spectrum of biological properties
like fungicidal [1], antibacterial [2], anti-inflammatory
[3], antitubercular [4], antitumor [5], herbicidal [6], anti-
feedent [7], and antiviral [8] activities. Ureido derivatives
of 5-amino-3-methylisoxazole-4-carboxylic acid were found
to have a significant antileukemic activity [9]. Structure-
activity relationship studies of 5-methyl-3-substituted
phenylisoxazole-4-carboxamides revealed that they are
potent antagonists for secretagogue receptors [10]. It
was also demonstrated that the C¼O group at the C-(4)
is the most adaptable site for chemical change and is an
area that greatly influences potency spectrum and safety.
Triazole heterocycles are found to be potent antimicrobial
[11], antiviral [12], and antiproliferative [13] agents. Iso-
xazole coupled triazoles were reported as antimicrobial,
antifungal [14], and NK-1 antagonists [15]. The pharma-
ceutical importance of triazoles and isoxazoles has
prompted the design and synthesis of various triazole sub-
stituted isoxazoles. In an attempt to find new and potent anti-
microbials, we report the synthesis of a few (1-(substituted
alkyl)-1H-1,2,3-triazol-4-yl)methyl 5-methyl-3-(substituted
phenyl)-isoxazole-4-caroboxylate. We have focused on in-
troduction of new 1,2,3-triazole ring on C-4 of carboxylic
acid group of isoxazole by click reaction.
RESULT AND DISCUSSION
The focus of this investigation is on the development
of a few N-substituted (1H-1,2,3-triazole-4-yl)methyl 5-
© 2012 HeteroCorporation

622
P. V. Ramana and A. R. Reddy
Vol 49
Scheme 1. One pot synthesis of 5-methyl-3-substituted phenyl isoxazole-4-carboxylic acids from benzaldehyde/substituted benzaldehydes. Reagents and
conditions: a = hydroxylamine hydrosulfate, MeOH, Na2CO3, reflux; b = Cl2 gas, 0–5ꢀC; c = methylacetoacetate, MeOH, NaOH, reflux; d = aqueous NaOH
(25%), reflux.
spectrum of IIb and IId exhibited molecular ion peaks at
[M + 2]+ (30%) due to the presence of one Cl atom. Simi-
larly, compound IIc has given molecular ion peaks at [M]+
(38%), [M + 2]+ (56%) and [M + 4]+(6%) due to the presence
of two chlorine atoms.
of methyl group on the isoxazole, whereas two other
singlets at 5.30 and 5.48 ppm are due to methylene
protons attached to the triazole ring at N-1 and C-4. The
remaining four triplet signals at 3.47, 3.53, 3.59, and
3.63 ppm are assigned to morpholine ring H-atoms.
Instead of two triplet signals expected for morpholine
protons, four triplet signals were observed. Probably this
may be due to a stable chair conformation in which the
bulky triazole ring is locked in the equatorial position
there by differentiating the equatorial and axial on each
methylene carbon in the morpholine ring. The bulkier
triazole ring prevents the ring flipping and restricting the
interconversion of axial-equatorial protons resulting in
four triplet signals. The two equatorial protons of the
methylene adjacent to oxygen of morpholine resonating
at 5.48 ppm, whereas the two axial protons adjacent
oxygen resonated at 5.3 ppm. Similarly, the two equato-
rial protons of the methylene adjacent to nitrogen in
morpholine have resonated at 3.59 ppm, whereas those
of axial protons resonated at 3.53 ppm. 13C-NMR data
is also in agreement with the proton NMR data. The
13C-NMR spectra show four different chemical shifts
for the four —CH2— groups in the morpholine ring.
Two C-atoms adjacent to the N-atom are placed one
above the plane and other one below the plane. These
two carbons are resonated around 42.5–45.8. Similarly,
the two carbons, which are adjacent to oxygen, gave two
peaks around 66 ppm. Similar results were obtained in
Vb1, Vc1, and Vd1.
IVa–IVd reacts with azidomethylbenzene (2) under
click reaction condition to form triazolo isoxazoles
(Va2–Vd2). The benzylic protons in Va2–Vd2 resonated
at 5.60, 5.59, 5.60, and 5.59 ppm, respectively, in 1H-NMR.
This indicates the formation of triazole ring. Similarly, these
benzylic carbons exhibited signals at 57.9, 58.0, 57.9,
and 57.8 ppm for Va2, Vb2, Vc2, and Vd2, respectively,
in 13C-NMR. Triazoles (Va3–Vd3) were obtained from
IVa to IVd on reacting with 2-(4-azidobutyl)isoindoline-
1,3-dione. It has been found that the pseudo molecular
ions of Va3–Vd3 [M + H]+ and [M + Na]+ were matched
with their respective molecular weights. The four
aromatic protons in indoline ring have shown a multiplet
signal at 7.82–7.84 ppm, whereas the isoxazole attached
Compounds IIa–IId on reaction with PCl5 produced the
corresponding acid chlorides (IIIa–d). The formation of
the respective acid chlorides was confirmed by the disap-
1
pearance of carboxylic acidic proton signal in H-NMR
of IIIa–d.
Compounds (IIIa–IIId) on reaction with propargylic
alcohol in presence of Et3N yielded propargylic esters
(IVa–IVd). The 1H-NMR spectrum of compound IVa
showed signals at d 2.48 and 4.79 due to propargylic and
terminal alkyne protons. These two protons underwent
propargylic 4J coupling and was split into doublet and trip-
let. Although separated by four bond lengths, these two
4
types of protons behaved as a spin system with a J value
1
of 2.4 Hz. Similar signals also appeared in the H-NMR
spectra of IVb–IVd. The IR spectra of these compounds
exhibited a new weak absorption maximum at around
2100 cmꢁ1 characteristic of υcꢂc, indicating the formation
of propargylic ester. In the 13C-NMR spectra of IVa–IVd,
the propargylic CH2 resonated around 52 ppm and the two
triple bonded carbons resonated around 75 ppm.
These propargylic esters (IVa–IVd) on reaction with
different azides (1–5, 1, 2-azido-1-morpholineethanone;
2, benzylazide; 3, 2-(4-azidobutyl)isoindole-1,3-dione; 4,
n-butyl azide; 5, allyl azide) in the presence of Cu(I) gener-
ated by sodium ascorbate (click condition), undergo [2 + 3]
dipolar cycloaddition reactions and form Va–d (Scheme 2).
The formation of triazoles is proved by spectroscopic
analysis. The IR spectrum of V reveals the disappearance
1
of CꢂC stretching frequency. In the H-NMR spectrum,
H-C-(5) of the newly formed triazole ring resonated around
d 7.50, whereas it was at d 2.77 acetylenic in its precursor
IV in CDCl3. However, this proton shifted down field in a
more polar aprotic solvent like DMSO-(D6). For example,
the C-5 proton of Vb1 resonated at 7.59 ppm in CDCl3
and at 7.90 ppm in DMSO-(D6).
The proton NMR of Va1 contains seven aliphatic
signals at 2.69, 3.42, 3.53, 3.59, 3.63, 5.30, and 5.48 ppm.
The singlet signal at 2.69 ppm is due to the protons
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis of 1,2,3-Triazole Substituted Isoxazoles via Copper (I) Catalyzed Cycloaddition
623
Scheme 2. Synthesis of isoxazole coupled triazoles. Reagents and conditions: a = PCl5, rt; b = Propargylic alcohol, TEA, DCM, 0ꢀC—r.t.; c = R00N3,
t-BuOH-H2O (7:3), Cu2SO4, sodium ascorbate, r.t.
EXPERIMENTAL
phenyl protons gave a signal at slightly up field less than
7.53 ppm. A new peak at d 168 in these compounds in
13C-NMR reveals the presence of imide carbon of phthali-
mide and formation of triazolo isoxazoles. 1-Azidobutane
is a common precursor for the preparation of Va4–Vd4.
In these butyl substituted triazole derivatives, the methyl
protons have shown a triplet signal at 1.00 ppm. Methylenic
protons attached to nitrogen gave triplet signal at around
4.28 ppm and middle four methylenic protons resonated
The reagents and solvents were of analytical grade and were
used without further purification unless otherwise mentioned.
Thin layer chromatography (TLC) was carried out on aluminum
sheets coated with silica gel 60 F254 (Merck). TLC plates were
inspected under UV light. Micro-analytical data were obtained
by using a Perkin-Elmer 240c analyzer. IR spectra were recorded
with a Perkin-Elmer-1700 spectrophotometer. 1H-NMR and
13C-NMR spectra were measured on a Bruker Avance 400 MHz
spectrometer. Coupling constants have been assigned and listed
without duplication in the 1H-NMR description of the synthesized
compounds. ESI-MS were recorded on an LCQ system (Finngan
MAT, USA) using MeOH as the mobile phase. M. P. were
recorded on a Polmon MP 96.
1
at around d 1.31 and 1.83 as multiplet in H-NMR of
Va4–d4. The 13C-NMR of Va4–d4 represents the presence
of alkyl side chain to triazole. The carbon attached to
nitrogen resonated at around 50 ppm, the terminal carbon
at around 13 ppm, and middle two carbons at around 19
and 32 ppm, respectively. Compounds IVa–IVd on reaction
with 3-azidoprop-1-ene yielded triazoles, Va5–Vd5 under
General experimental procedure for the preparation of 5-
methyl-3-(phenyl/substituted phenyl)-isoxazole-4-carboxylic
1
acid (IIa–IId). To
a solution of benzaldehyde (Ia) or
click condition. The H-NMR of Va5–Vd5 clearly confirms
substituted benzaldehyde (Ib–Id) (1 equiv), four times of
methanol hydroxylamine hydrosulfate (1.4 equiv) was added
and stirred for 30 min. The reaction mixture was slowly
converted to a clear solution. Later, the pH was adjusted to 8–9
with Na2CO3 and refluxed for 0.5 h. Subsequently, it was
cooled to 0–5ꢀC and was chlorinated by passing Cl2 gas over a
period of 1–2 h. The excess Cl2 gas was removed by passing
the nitrogen and the highly acidic solution pH was adjusted to
1–2 by using Na2CO3 at 0ꢀC. In another flask, sodium salt of
methylacetoacetate was prepared by addition of 1.4 equiv of
NaOH to a solution of methyl acetoacetate (1.4 equiv) in four times
volume of methanol at 0–5ꢀC and stirred for 30 min by maintaining
the pH at 10. The precipitate, sodium salt of methylaceto acetate
formed during the course of reaction in methanol was added to
chloro compound during a period 1 h at 0–5ꢀC, and stirred for 1
h at r.t. by maintaining the pH 9. Subsequently, the pH was
adjusted to 11–13 with aqueous 25% NaOH solution at r.t. and
refluxed the reaction mixture for 1 h. The methanol was distilled
then added 5 times of water and adjusted the pH to 2–2.5 with
20% H2SO4. The compound was filtered, washed with hot water,
and recrystallized in methanol to afford pure product.
the formation of triazoles. The N-1 attached methylene protons
appeared as a doublet signal around 6.0 ppm. The vinyl cis
protons have always resonated at up field than the trans protons.
Morpholine substituted triazoles (Va1–Vd1) melted at
higher temperature than the benzylazido (Va2–Vd2) and
phthalyl-butylazido triazoles (Va3–Vd3). However, the
butylazido (Va4–Vd4) and allylazido (Va5–Vd5) substi-
tuted triazoles are liquids.
CONCLUSIONS
In summary, we have successfully demonstrated a
simple and convenient route for the synthesis of 1,2,3-
triazole substituted isoxazoles by using the Cu(I) cata-
lyzed [2 + 3] dipolar cycloaddition reaction. In addition
to its simplicity and mild reaction conditions, this method
provides a wide range of triazoles in good yields in a
single step operation.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

624
P. V. Ramana and A. R. Reddy
Vol 49
5-Methyl-3-phenyl-isoxazole-4-corboxylic acid (IIa). Yield:
1H-NMR (CDCl3, 400 MHz): d 2.85 (s, 3H), 7.35–7.41 (m, 3H).
13C-NMR (CDCl3, 100 MHz): d 14.2, 114.0, 127.0, 128.0, 131.7,
135.6, 158.1, 158.6, 177.7; Mass (ES): m/z 290 [M + H]+. Anal.
Calcd. for C11H6Cl3NO2: C, 45.47; H, 2.08; N, 4.82%. Found: C,
45.61; H, 2.03, N, 4.90%.
82%; M.p.: 189–190ꢀC; IR (KBr): υ 3075, 3020, 2878, 2689,
2613, 1689, 1598, 1471, 1424, 1338, 1162, 1122 cmꢁ1; 1H-NMR
(CDCl3, 400 MHz): d 2.72 (s, 3H), 7.41–7.47 (m, 3H), 7.63
(d, 2H, J = 6.8 Hz) 13.12 (br. S, 1H). 13C-NMR (CDCl3, 100
MHz): d 13.5, 107.5, 127.8, 128.1, 129.4, 129.8, 163.2, 167.1,
175.2; Mass (ES): m/z 204 [M + H]+. Anal. Calcd. for C11H9NO3:
C, 65.02; H, 4.46; N, 6.89%. Found: C, 64.88; H, 4.32, N, 6.95.
3-(2-Chlorophenyl)-5-methyl-isoxazole-4-corboxylic acid
(IIb). Yield: 85%; M.p.: 193–196ꢀC; IR (KBr): υ 3017,
2881, 2686, 2607, 1690, 1603, 1574, 1456, 1405, 1317,
3-(2-Chloro-6-flourophenyl)-5-methyl-isoxazole-4-corbonyl
chloride (IIId). Yield: 88%; M.p.: 181–184ꢀC; IR (KBr): υ 3054,
3010, 1757, 1693, 1576, 1514, 1449, 1393, 1290, 1250, 1185,
1
1162 cmꢁ1; H-NMR (CDCl3, 400 MHz): d 2.86 (s, 3H), 7.14
(t, 1H, J = 8.0 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.40–7.46
(m, 1H). 13C-NMR (CDCl3, 100 MHz): d 14.2, 109.0,
113.9, 116.5, 125.4, 132.2, 135.2, 155.0, 158.6, 162.1, 177.6;
Mass (ES): m/z 274 [M + H]+. Anal. Calcd. for C11H6Cl2FNO3:
C, 48.21; H, 2.21; N, 5.11%. Found: C, 48.10; H, 2.08; N, 5.11%.
General procedure for the preparation of 5-methyl-3-
substituted phenyl-isoxazole-4-carboxyl propargyl esters
(IVa–IVd). To a cold solution (0ꢀC) of substituted isoxazole
carboxyl chloride (IIIa–IIId) (2.0 mmol) in DCM (20 mL),
triethylamine (2.3 mmol) and propargylic alcohol (2.8 mmol)
were added. The resulting solution was stirred at r.t. for 2 h.
The reaction mixture was diluted with water and extracted
with DCM (3ꢃ 20 mL). The organic layers were combined,
and the solvent was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (hexane:
ethyl acetate 8:2) to afforded pure product.
Prop-2-ynyl 5-methyl-3-phenylisoxazole-4-carboxylate
(IVa). Yield: 84%; M.p.: 55–58ꢀC; IR (KBr): υ 3290, 3063, 2949,
2129, 1730, 1599, 1448,1425, 1369, 1304, 1249, 1151, 1132,
1095 cmꢁ1; 1H-NMR (CDCl3, 400 MHz): 2.48 (t, 1H, J = 2.4 Hz),
2.77 (s, 3H), 4.79 (d, 2H, J = 2.4 Hz), 7.38–7.44 (m, 3H), 7.64
(d, 2H, J = 6.9 Hz). 13C-NMR (CDCl3, 300 MHz): d 13.4, 51.9,
75.1, 107.8, 128.0, 128.2, 129.3, 129.7, 160.9, 162.4, 176.2;
Mass (ES): m/z 242 [M + H]+, 264 [M + Na]+. Anal. Calcd. for
C14H11NO3: C, 69.70; H, 4.60; N, 5.81%. Found: C, 69.57; H,
4.41; N, 5.79%.
1250, 1162, 1104 cmꢁ1
;
1H-NMR (CDCl3, 400 MHz):
d 2.75 (s, 3H), 7.38–7.46 (m, 4H), 12.52 (br. s, 1H). 13C-NMR
(CDCl3, 100 MHz): d 13.0, 110.2, 126.3, 128.8, 129.2, 130.4,
130.9, 133.9, 160.9, 162.9, 174.9; Mass (ES): m/z 238 [M + H]+.
Anal. Calcd. for C11H8ClNO3: C, 55.60; H, 3.39; N, 5.89%.
Found: C, 55.48; H, 3.32, N, 5.99%.
3-(2,6-Dichlorophenyl)-5-methyl-isoxazole-4-corboxylic acid
(IIc). Yield: 79%; M.p.: 225–226ꢀC; IR (KBr): υ 3060, 2927,
2675, 2606, 1695, 1601, 1560, 1514, 1463, 1383, 1320, 1262,
1194 cmꢁ1 1H-NMR (CDCl3, 400 MHz): d 2.79 (s, 3H),
;
7.29–7.41 (m, 3H), 12.86 (br. S, 1H). 13C-NMR (CDCl3, 100 MHz):
d 13.0, 110.0, 127.6, 128.4, 130.7, 135.2, 158.7, 162.4, 175.3;
Mass (ES): m/z 272 [M + H]+. Anal. Calcd. for C11H7Cl2NO3:
C, 48.56; H, 2.59; N, 5.15%. Found: C, 48.41; H, 2.45; N,
5.15%.
3-(2-Chloro-6-flourophenyl)-5-methyl-isoxazole-4-corboxylic
acid (IId). Yield: 76%; M.p.: 206–208ꢀC; IR (KBr): υ 3072,
2895, 2686, 2607, 1689, 1605, 1517, 1454, 1379, 1316, 1250,
1
1188, 1161 cmꢁ1; H-NMR (CDCl3, 400 MHz): d 2.75 (s, 3H),
7.12 (t, 1H, J = 8.1 Hz ), 7.31 (d, 1H, J = 7.6 Hz), 7.40–7.46
(m, 1H), 12.91 (br. S, 1H). 13C-NMR (CDCl3, 300 MHz):
d 13.2, 110.3, 114.0, 117.8, 125.0, 131.2, 135.0, 155.6, 159.5,
162.6, 175.4; Mass (ES): m/z 256 [M + H]+. Anal. Calcd. for
C11H7ClFNO3: C, 51.68; H, 2.76; N, 5.48%. Found: C, 51.41;
H, 2.73; N, 5.61%.
General experimental procedure for the preparation of
5-methyl-3-substituted phenyl-isoxazole-4-carbonyl chloride
(IIIa–IIId). To the compound IIa–IId (25 g), PCl5 (25 g) at r.t.
was added and heated to 45ꢀC to become clear solution. It was
stirred for 1 h and the byproduct POCl3 distilled out at reduced
pressure. To the residue 75 mL of hexane was added for
crystallization and filtered.
Prop-2-ynyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate
(IVb). Yield: 72%; M.p.: 65–67ꢀC; IR (KBr): υ 3292, 3063, 2949,
1
2131, 1720, 1604, 1575, 1510, 1440, 1309, 1099 cmꢁ1; H-NMR
(CDCl3, 400 MHz): d 2.41 (t, 1H, J = 2.4 Hz), 2.79 (s, 3H), 4.71
(d, 2H, J = 2.4 Hz), 7.28–7.48 (m, 4H). 13C-NMR (CDCl3, 100
MHz): d 13.0, 51.9, 74.8, 74.9, 109.2, 126.4, 128.5, 129.4, 130.6,
130.9, 134.0, 160.5, 160.6, 175.4; Mass (ES): m/z 276 [M + H]+,
297 [M + Na]+. Anal. Calcd. for C14H10ClNO3: C, 69.99; H, 3.66;
N, 5.08%. Found: C, 69.99; H, 3.51; N, 5.21%.
5-Methyl-3-phenyl-isoxazole-4-corbonyl chloride (IIIa).
Yield: 90%; B.p.: 115–117ꢀC (3 Torr); IR (neat): υ 3065,
Prop-2-ynyl 3-(2,6-chlorophenyl)-5-methylisoxazole-4-
carboxylate (IVc). Yield: 79%; M.p.: 62–65ꢀC; IR (KBr):
υ 3294, 3076, 2937, 2130, 1729, 1592, 1561, 1455, 1424, 1363,
3010, 1741, 1689, 1605, 1462, 1316, 1250, 1157, 1116 cmꢁ1
;
1H-NMR (CDCl3, 400 MHz): d 2.79 (s, 3H), 7.42–7.46 (m, 3H),
7.62 (d, 2H, J = 7.6 Hz). 13C-NMR (CDCl3, 100 MHz): d 13.6,
107.5, 128.0, 128.1, 129.3, 129.8, 162.6, 166.3, 177.4; Mass
(ES): m/z 222 [M + H]+. Anal. Calcd. for C11H8ClNO2: C,
59.61; H, 3.64; N, 6.32%. Found: C, 59.58; H, 3.73; N, 6.31%.
3-(2-Chlorophenyl)-5-methyl-isoxazole-4-corbonyl chloride
(IIIb). Yield: 93%; M.p.: 45–48ꢀC; IR (KBr): υ 3061, 3005,
1303, 1248, 1194, 1154, 1115, 1091 cmꢁ1 1H-NMR (CDCl3,
;
400 MHz): d 2.43 (t, 1H, J = 2.4 Hz), 2.85 (s, 3H), 4.72 (d, 2H,
J = 2.4 Hz), 7.35–7.43 (m, 3H). 13C-NMR (CDCl3, 100 MHz):
d 13.2, 52.0, 74.9, 75.0, 108.9, 127.7, 128.0, 130.9, 135.4,
158.5, 160.1, 176.0; Mass (ES): m/z 310 [M + H]+, 311 [M + 2]+,
313 [M + 4]+. Anal. Calcd. for C14H9ClNO3: C, 57.26; H, 3.09;
N, 4.52%. Found: C, 57.27; H, 3.09; N, 4.68%.
1732, 1685, 1604, 1458, 1309, 1258, 1141, 1117 cmꢁ1
;
1H-NMR (CDCl3, 400 MHz): d 2.79 (s, 3H), 7.33–7.40 (m, 4H).
13C-NMR (CDCl3, 300 MHz): d 13.9, 114.8, 126.7, 127.4,
129.6, 131.0, 131.3, 134.2, 158.9, 160.2, 176.7; Mass (ES): m/z
256 [M + H]+. Anal. Calcd. for C11H7Cl2NO2: C, 51.59; H, 2.76;
N, 5.47%. Found: C, 51.42; H, 2.83; N, 5.47%.
Prop-2-ynyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-
4-carboxylate (IVd). Yield: 68%; M.p.: 73–75ꢀC; IR (KBr):
υ 3300, 3086, 2951, 2131, 1732, 1612, 1574, 1514, 1454, 1369,
1304, 1249, 1186, 1099 cmꢁ1 1H-NMR (CDCl3, 400 MHz):
;
d 2.41 (t, 1H, J = 2.4Hz), 2.81 (s, 3H), 4.71 (d, 2H, J = 2.7 Hz),
7.11 (t, 1H, J = 8.2 Hz), 7.29 (d, 1H, J = 7.6 Hz), 7.37–7.45
(m, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.2, 52.0, 75.0, 109.2,
113.9, 117.2, 125.1, 131.5, 135.1, 154.4, 160.1, 162.0, 176.0; Mass
3-(2,6-Dichlorophenyl)-5-methyl-isoxazole-4-corbonyl chloride
(IIIc). Yield: 84%; M.p.: 88–89ꢀC; IR (KBr): υ 3089, 3002, 1757,
1689, 1562, 1498, 1432, 1390, 1290, 1249, 1195, 1145 cmꢁ1
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis of 1,2,3-Triazole Substituted Isoxazoles via Copper (I) Catalyzed Cycloaddition
625
(ES): m/z 294 [M + H]+, 295 [M + 2]+. Anal. Calcd. for
C14H9ClFNO3: C, 57.26; H, 3.09; N, 4.77%. Found: C, 57.32; H,
2.91; N, 4.91%.
(1-Allyl-1H-1,2,3-triazol-4-yl)methyl 5-methyl-3-phenylisoxa-
zole-4-carboxylate (Va5). Yield: 78%; IR (neat): υ 3144,
3072, 2930, 1722, 1601, 1577, 1448, 1423, 1304, 1251, 1226,
1151, 1099, 1049 cmꢁ1 1H-NMR (DMSO-d6, 400 MHz):
;
General experimental procedure for the synthesis of
(Va–Vd). Compound (IVa–IVd) (2 mmol) and azides (1–5)
(2.2 mmol) were dissolved in10 mL of tert-butanol-H2O (7:3 V/V).
To this mixture, CuSO4ꢄ5H2O (25 mg, 0.1 mmol) and sodium
ascorbate (39 mg, 0.2 mmol) aqueous solutions were added
and stirred for overnight at rt. The reaction mixture was
poured into 25 mL of water and was extracted with ethyl
acetate (3ꢃ 20 mL). The organic layers were combined and
washed with water (20 mL), dried over anhydrous Na2SO4.
The solvent was evaporated in vacuo to give the pure product.
Spectral data of Va–Vd. (1-(2-Morpholino-2-oxoethyl)-1H-
1,2,3-triazol-4-yl)methyl 5-methyl-3-phenylisoxazole-4-caroboxylate
(Va1). Yield: 86%; M.p.: 128–130ꢀC; IR (KBr): υ 3142, 2931, 1720,
d 2.70 (s, 3H), 5.02 (d, 2H, J = 6.0 Hz), 5.20 (d, 1H,
J = 15.6 Hz), 5.31 (d, 1H, J = 8.7 Hz), 5.33 (s, 2H),
5.98–6.08 (m, 1H), 7.38–7.52 (m, 3H), 7.58 (d, 2H,
J = 7.6 Hz), 8.00 (s, 1H). 13C-NMR (CDCl3, 100 MHz):
d 13.4, 52.5, 57.9, 108.0, 120.0, 123.1, 127.9, 128.5, 129.3,
129.5, 131.0, 142.6, 161.6, 162.3, 176.1; Mass (ES): m/z 325
[M + H]+, 347 [M + Na]+. Anal. Calcd. for C17H16N4O3: C,
62.95; H, 4.97; N, 17.27%. Found: C, 63.18; H, 4.92, N, 17.27%.
(1-(2-Morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl 3-
(2-chlorophenyl)-5-methylisoxazole-4-caroboxylate (Vb1). Yield:
89%; M.p.: 136–138ꢀC; IR (KBr): υ 3131, 2923, 2855, 1720,
1667, 1649, 1600, 1439, 1314, 1242, 1198, 1106, 1056 cmꢁ1
;
1H-NMR (DMSO-d6, 400 MHz): d 2.73 (s, 3H), 3.44 (t, 2H,
J = 4.6 Hz), 3.52 (t, 2H, J = 4.6 Hz), 3.60 (t, 2H, J = 4.6 Hz),
3.64 (t, 2H, J = 4.6 Hz), 5.21 (s, 2H), 5.43 (s, 2H), 7.39–7.52
(m, 4H), 7.90 (s,1H). 13C-NMR (DMSO, 100 MHz): d 13.1,
42.6, 45.7, 50.6, 57.8, 66.3, 109.3, 124.9, 126.5, 128.5, 129.4,
130.6, 130.9, 133.9, 142.8, 160.6, 161.1, 163.3, 175.5; Mass
(ES): m/z 446 [M + H]+, 468 [M + Na]+. Anal. Calcd. for
C20H20ClN5O5: C, 53.88; H, 4.52; N, 15.71%. Found: C, 53.61;
H, 4.23; N, 16.00%.
1667, 1649, 1600, 1439, 1314, 1242, 1198, 1106, 1056 cmꢁ1
;
1H-NMR (DMSO-d6, 400 MHz): d 2.69 (s, 3H), 3.42 (t, 2H,
J = 4.2 Hz), 3.53 (t, 2H, J = 4.2 Hz), 3.59 (t, 2H, J = 4.2 Hz),
3.63 (t, 2H, J = 4.2 Hz), 5.30 (s, 2H), 5.48 (s, 2H), 7.40–7.51
(m, 3H), 7.57 (d, 2H, J = 7.2 Hz), 7.98 (s, 1H). 13C-NMR
(CDCl3, 100 MHz): d 13.7, 42.5, 45.6, 50.6, 57.8, 66.2, 66.5,
107.9, 125.6, 128.0, 128.3, 129.4, 129.7, 142.3, 161.5, 162.6,
163.3, 176.4; Mass (ES): m/z 412 [M + H]+, 434 [M + Na]+.
Anal. Calcd. for C20H21N5O5: C, 58.39; H, 5.14; N, 17.02%.
Found: C, 58.02; H, 5.06; N, 17.35%.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 3-(2-chlorophenyl)-5-
methylisoxazole-4-carboxylate (Vb2). Yield: 82%; M.p.:
100–102ꢀC; IR (KBr): υ 3145, 2965, 1721, 1603, 1497,
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 5-methyl-3-phenyli-
soxazole-4-carboxylate (Va2). Yield: 92%; M.p.: 105–107ꢀC;
IR (KBr): υ 3130, 3087, 2952, 1762, 1710, 1600, 1579, 1459,
1439, 1415, 1343, 1305, 1253, 1155, 1089 cmꢁ1 1H-NMR
;
1441, 1391, 1363, 1305, 1260, 1228, 1165, 1092, 1040 cmꢁ1
;
(DMSO-d6, 400 MHz): d 2.72 (s, 3H), 5.18 (s, 2H), 5.59 (s, 2H),
7.27–7.61 (m, 9H), 7.92 (s, 1H). 13C-NMR (CDCl3, 100 MHz):
d 12.9, 54.0, 58.0, 109.4, 123.0, 126.3, 127.9, 128.6, 128.7,
129.0, 129.2, 130.5, 130.9, 133.8, 134.6, 142.5, 160.5, 161.0,
175.5; Mass (ES): m/z 408 [M + H]+, 431 [M + Na]+. Anal. Calcd.
for C21H17ClN4O3: C, 61.69; H, 4.19; N, 13.70%. Found: C, 61.32;
H, 3.99, N, 13.70%.
1H-NMR (DMSO-d6, 400 MHz): d 2.68 (s, 3H), 5.29 (s, 2H),
5.60 (s, 2H), 7.28–7.41 (m, 8H), 7.58 (d, 2H, J = 6.8 Hz),
8.12 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.6, 54.2, 57.9,
108.2, 123.1, 127.9, 128.1, 128.4, 128.8, 129.1, 129.3, 129.7,
134.4, 161.6, 162.4, 176.4; Mass (ES): m/z 375 [M + H]+, 397
[M + Na]+. Anal. Calcd. for C21H18N4O3: C, 67.37; H, 4.85;
N, 14.96%. Found: C, 67.03; H, 4.51; N, 14.85%.
(1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1H-1,2,3-triazol-4-yl)
methyl 3-(2-chlorophenyl)-5-methylisoxazole-4-carboxylate (Vb3).
Yield: 91%; M.p.: 132–135ꢀC; IR (KBr): υ 3131, 3093, 2952,
1769, 1710, 1606, 1466, 1439, 1398, 1305, 1265, 1158, 1097
(1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1H-1,2,3-triazol-4-yl)
methyl 5-methyl-3-phenylisoxazole-4-3-carboxylate (Va3). Yield:
96%; M.p.: 118–120ꢀC; IR (KBr): υ 3132, 3095, 2961, 1764,
1730, 1712, 1612, 1552, 1423, 1391, 1358, 1296, 1154, 1116,
cmꢁ1 1H-NMR (DMSO-d6, 400 MHz): d 1.51–1.58 (m, 2H),
;
1047 cmꢁ1 1H-NMR (DMSO-d6, 400 MHz): d 1.52–1.61
;
1.78–1.83 (m, 2H), 2.73 (s, 3H), 3.64 (t, 2H, J = 6.2 Hz), 4.38
(t, 2H, J = 6.0 Hz), 5.15 (s, 2H), 7.39–7.47 (m, 4H), 7.80–7.88
(m, 4H), 7.91 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 12.9,
25.5, 27.3, 36.8, 49.5, 58.0, 109.4, 123.1, 126.3, 128.7, 129.3,
130.5, 131.0, 132.1, 133.8, 160.5, 161.1, 168.0, 175.4; Mass
(ES): m/z 520 [M + H]+, 542 [M + Na]+. Anal. Calcd. for
C26H22ClN5O5: C, 60.06; H, 4.26; N, 13.47%. Found: C, 59.82;
H, 3.99, N, 13.39%.
(m, 2H), 1.78–1.85 (m, 2H), 2.63 (s, 3H), 3.60 (t, 2H, J = 5.8 Hz),
4.40 (t, 2H, J = 6.0 Hz), 5.28 (s, 2H), 7.38–7.46 (m, 3H),
7.55 (d, 2H, J = 7.1 Hz), 7.80–7.86 (m, 4H), 8.02 (s, 1H).
13C-NMR (CDCl3, 100 MHz): d 13.5, 25.3, 27.6, 37.1, 49.4,
58.1, 108.7, 123.3, 123.8, 127.9, 128.1, 129.7, 130.0, 131.9,
134.3, 161.9, 162.7, 168.2, 177.0; Mass (ES): m/z 486 [M + H]+,
508 [M + Na]+. Anal. Calcd. for C26H23N5O5: C, 64.32; H,
4.78; N, 14.42%. Found: C, 64.03; H, 4.50; N, 14.41%.
(1-Butyl-1H-1,2,3-triazol-4yl)methyl 3-(2-chlorophenyl)-5-
methylisoxazole-4-carboxylate (Vb4). Yield: 90%; IR (neat):
υ 2964, 2935, 1728, 1702, 1608, 1454, 1311, 1151, 1103,
(1-Butyl-1H-1,2,3-triazol-4yl)methyl 5-methyl-3-phenylisoxa-
zole-4-carboxylate (Va4). Yield: 76%; IR (neat): υ 3142, 3053,
2961, 1724, 1601, 1574, 1448, 1421, 1304, 1249, 1151, 1099,
985 cmꢁ1 1H-NMR (DMSO-d6, 400 MHz): d 0.93 (t, 2H,
;
1049 cmꢁ1
;
1H-NMR (DMSO-d6, 400 MHz): d 0.89 (t, 3H,
J = 5.4 Hz), 1.28–1.34 (m, 2H) 1.79–1.86 (m, 2H), 2.73
(s, 3H), 4.28 (t, 2H, J = 5.4 Hz), 5.24 (s, 2H), 7.32 (d, 2H,
J = 7.2 Hz), 7.37 (s, 2H), 7.38 (s, 1H). 13C-NMR (CDCl3,
100 MHz): d 13.3, 13.4, 19.6, 32.1, 50.1, 58.0, 109.3, 126.6,
128.4, 129.3,130.7, 131.0, 133.9, 160.6, 161.3, 175.6; Mass
(ES): m/z 375 [M + H]+, 398 [M + Na]+. Anal. Calcd. for
J = 5.2 Hz), 1.20–1.27 (m, 2H), 1.74–1.82 (m, 2H), 2.70 (s, 3H),
4.36 (t, 2H, J = 5.2 Hz), 5.28 (s, 2H), 7.39–7.51 (m, 3H), 7.59
(d, 2H, J = 6.8 Hz) 8.03 (s, 1H). 13C-NMR (CDCl3, 100 MHz):
d 13.2, 13.4, 19.6, 32.0, 50.1, 57.9, 108.0, 127.9, 128.5, 129.3,
129.5, 161.6, 162.4, 176.2; Mass (ES): m/z 341 [M + H]+, 363
[M + Na]+. Anal. Calcd. for C18H20N4O3: C, 63.52; H, 5.92; N,
16.46%. Found: C, 63.12; H, 6.08; N, 16.81%.
C
18H19ClN4O3: C, 57.68; H, 5.11; N, 14.95%. Found: C,
57.32; H, 4.97; N, 14.69%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

626
P. V. Ramana and A. R. Reddy
Vol 49
(1-Allyl-1H-1,2,3-triazol-4-yl)methyl 3-(2-chlorophenyl)-5-
(1-Allyl-1H-1,2,3-triazol-4-yl)methyl 3-(2,6-dichlorophenyl)-
5-methylisoxazole-4 carboxylate (Vc5). Yield: 90%; IR (neat):
υ 3146, 3086, 2932, 1726, 1676, 1608, 1562, 1433, 1302,
methylisoxazole-4 carboxylate (Vb5). Yield: 79%; IR (neat):
υ 3148, 3082, 2962, 1728, 1676, 1608, 1508, 1444, 1309,
1
1267, 1151, 1105, 1051 cmꢁ1; H-NMR (DMSO-d6, 400 MHz):
1246, 1195, 1165, 1051 cmꢁ1 1H-NMR (DMSO-d6, 400
;
d 2.73 (s, 3H), 5.02 (d, 2H, J = 5.8 Hz), 5.15 (d, 1H, J = 15.9 Hz),
5.20 (s, 2H), 5.28 (d, 1H, J = 8.2 Hz), 5.98–6.08 (m, 1H),
7.38–7.44 (m, 2H), 7.47 (d, 2H, J = 7.8 Hz), 7.83 (s, 1H).
13C-NMR (CDCl3, 100 MHz): d 13.0, 52.4, 58.0, 109.3,
119.9, 122.9, 126.4, 128.6, 129.2, 130.6, 130.9, 131.1, 133.9,
142.4, 160.5, 161.0, 175.4; Mass (ES): m/z 358 [M + H]+,
382 [M + Na]+. Anal. Calcd. for C17H15ClN4O3: C, 56.91;
H, 4.21; N, 15.62%. Found: C, 56.69; H, 4.01; N, 15.79%.
MHz): d 2.78 (s, 3H), 4.94 (d, 2H, J = 6.0 Hz), 5.25 (s, 2H),
5.30 (d, 1H, J = 15.0 Hz ), 5.37 (d, 1H, J = 9.0 Hz), 5.80–6.01
(m, 1H), 7.27–7.38 (m, 3H), 8.00 (s, 1H). 13C-NMR (CDCl3, 100
MHz): d 13.4, 52.7, 57.9, 109.0, 120.4, 123.2, 127.7, 128.0, 131.0,
135.3, 142.4, 158.4, 160.8, 176.1; Mass (ES): m/z 393 [M + H]+,
415 [M + Na]+. Anal. Calcd. for C17H14Cl2N4O3: C, 51.93; H,
3.59; N, 14.25%. Found: C, 51.74; H, 4.12; N, 14.10%.
(1-(2-Morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl 3-
(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-caroboxylate (Vd1).
Yield: 98%; M.p.: 141–143ꢀC; IR (KBr): υ 3132, 3076, 2992,
1721, 1667, 1646, 1573, 1460, 1425, 1305, 1274, 1240, 1140,
(1-(2-Morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl)methyl 3-
(2,6-dichlorophenyl)-5-methylisoxazole-4-caroboxylate (Vc1).
Yield: 92%; M.p.: 149–152ꢀC; IR (KBr): υ 3118, 3078, 2987,
1719, 1666, 1647, 1595, 1561, 1453, 1419, 1303, 1274,
1104, 1054 cmꢁ1 1H-NMR (DMSO-d6, 400 MHz): d 2.76
;
1239, 1156, 1109, 1052 cmꢁ1
;
1H-NMR (DMSO-d6, 400
(s, 3H), 3.45 (t, 2H, J = 5.0 Hz), 3.55 (t, 2H, J = 5.0 Hz), 3.59
(t, 2H, J = 5.0 Hz), 3.64 (t, 2H, J = 5.0 Hz), 5.22 (s, 2H), 5.48
(s, 2H), 7.32 (t, 1H, J = 8.1 Hz), 7.42 (d, 1H, J =7.9 Hz), 7.52–7.60
(m, 1H), 7.90 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.1, 42.6,
45.8, 50.6, 57.8, 66.3, 109.4, 113.9, 117.6, 124.9, 125.1, 131.4,
135.1, 143.2, 155.3, 160.7, 162.0, 163.3, 175.9; Mass (ES): m/z 465
[M + H]+, 487 [M + Na]+. Anal. Calcd. for C20H20ClFN5O5: C,
51.79; H, 4.13; N, 15.10%. Found: C, 51.74; H, 4.13; N, 15.00%.
MHz): d 2.75 (s, 3H), 3.45 (t, 2H, J = 4.6 Hz), 3.54 (t, 2H,
J = 4.6 Hz), 3.59 (t, 2H, J = 4.6 Hz), 3.63 (t, 2H, J = 4.6 Hz),
5.20 (s, 2H), 5.45 (s, 2H), 7.51–7.58 (m, 3H), 7.88 (s, 1H).
13C-NMR (CDCl3, 100 MHz): d 13.5, 42.5, 45.8, 50.8, 57.8,
66.6, 66.8, 109.2, 125.3, 127.8, 131.1, 135.2, 158.8, 160.7,
163.3, 176.2; Mass (ES): m/z 480 [M + H]+, 502 [M + Na]+.
Anal. Calcd. for C20H19Cl2N5O5: C, 50.01; H, 3.99; N,
14.58%. Found: C, 50.32; H, 4.09; N, 14.31%.
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 3-(2-chloro-6-fluoro-
phenyl)-5-methylisoxazole-4-carboxylate (Vd2). Yield: 84%; M.
p.: 94–96ꢀC; IR (KBr): υ 3141, 3088, 2983, 1717, 1613, 1598,
(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 3-(2,6-dichlorophenyl)-5-
methylisoxazole-4-carboxylate (Vc2). Yield: 76%; M.p.:
102–104ꢀC; IR (KBr): υ 3131, 3093, 2952, 1769, 1710,
1606, 1570, 1462, 1439, 1398, 1363, 1305, 1265, 1230,
1571, 1461, 1427, 1310, 1250, 1225, 1140, 1105, 1053 cmꢁ1
;
1H-NMR (DMSO-d6, 400 MHz): d 2.74 (s, 3H), 5.17 (s, 2H),
5.59 (s, 2H), 7.18–7.44 (m, 8H), 8.01 (s, 1H). 13C-NMR (CDCl3,
100 MHz): d 13.2. 54.1, 57.8, 109.2, 113.7, 114.0, 123.1, 124.9,
128.0, 129.0, 131.2, 131.3, 134.3, 134.8, 142.4, 158.8, 160.7,
162.1, 176.1; Mass (ES): m/z 427 [M + H]+, 449 [M + Na]+. Anal.
Calcd. for C21H17ClFN4O3: C, 59.09; H, 3.78; N, 13.13%.
Found: C, 58.97; H, 3.67; N, 13.47%.
1158, 1097, 1038 cmꢁ1 1H-NMR (DMSO-d6, 400 MHz):
;
d 2.73 (s, 3H), 5.17 (s, 2H), 5.60 (s, 2H), 7.25–7.49
(m, 8H), 7.95 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.1,
54.1, 57.9, 109.0, 122.9, 127.6, 128.0, 128.8, 129.1, 130.8,
134.5, 135.3, 142.6, 158.3, 160.7, 176.0; Mass (ES): m/z 443
[M + H]+, 465 [M + Na]+. Anal. Calcd. for C21H16Cl2N4O3:
C, 56.90; H, 3.64; N, 12.64%. Found: C, 56.88; H, 3.81; N,
12.75%.
(1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1H-1,2,3-triazol-4-yl)
methyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate
(Vd3). Yield: 87%; M.p.: 90–92ꢀC; IR (KBr): υ 3133, 3094,
2955, 1770, 1732, 1613, 1573, 1457, 1440, 1399, 1365, 1297,
(1-(4-(1,3-Dioxoisoindolin-2-yl)butyl)-1H-1,2,3-triazol-4-yl)methyl
3-(2,6-dichlorophenyl)-5-methylisoxazole-4-carboxylate (Vc3).
Yield: 81%; M.p.: 98–100ꢀC; IR (KBr): υ 3126, 3084,
2954, 1770, 1731, 1709, 1612, 1560, 1430, 1399, 1365,
1249, 1149, 1093, 1040 cmꢁ1 1H-NMR (DMSO-d6, 300
;
MHz): d 1.55–1.60 (m, 2H), 1.78–1.83 (m, 2H), 2.74 (s, 3H),
3.61 (t, 2H, J = 6.2 Hz), 4.38 (t, 2H, J = 6.0 Hz), 5.17 (s, 2H),
7.27 (t, 1H, J = 7.9 Hz), 7.36 (d, 1H, J = 7.6 Hz), 7.53–7.58
(m, 1H), 7.79–7.84 (m, 4H), 7.96 (s, 1H). 13C-NMR (CDCl3,
100 MHz): d 13.1, 25.5, 27.4, 36.8, 49.5, 57.8, 109.4, 114.1,
117.4, 123.2, 125.0, 131.3, 132.0, 133.9, 135.1, 155.3, 160.8,
162.0, 168.1, 175.9; Mass (ES): m/z 538 [M + H]+, 560 [M + Na]+.
Anal. Calcd. for C26H21ClFN5O5: C, 58.05; H, 3.93; N, 13.02%.
Found: C, 58.45; H, 3.71, N, 13.02%.
1296, 1165, 1108, 1040 cmꢁ1 1H-NMR (DMSO-d6, 400
;
MHz): d 1.52–1.60 (m, 2H), 1.78–1.83 (m, 2H), 2.74 (s, 3H),
3.61 (t, 2H, J = 6.0 Hz), 4.37 (t, 2H, J = 6.0 Hz), 5.14
(s, 2H), 7.47–7.52 (m, 3H), 7.80–7.86 (m, 4H), 7.92 (s, 1H).
13C-NMR (CDCl3, 100 MHz): d 12.7, 25.2, 27.6, 36.7, 49.3,
57.9, 108.3, 122.8, 125.2, 125.6, 130.4, 131.4, 133.7, 134.9,
158.3, 160.1, 167.0, 175.3; Mass (ES): m/z 554 [M + H]+, 576
[M + Na]+. Anal. Calcd. for C26H21Cl2N5O5: C, 56.33; H,
3.82; N, 12.63%. Found: C, 56.58; H, 4.05; N, 12.63%.
(1-Butyl-1H-1,2,3-triazol-4yl)methyl 3-(2-chloro-6-fluorophenyl)-
5-methylisoxazole-4-carboxylate (Vd4). Yield: 91%; IR (neat):
υ 3144, 3084, 2961, 1728, 1680, 1614, 1577, 1454, 1304, 1251,
(1-Butyl-1H-1,2,3-triazol-4yl)methyl 3-(2,6-dichlorophenyl)-5-
methylisoxazole-4-carboxylate (Vc4). Yield: 92%; IR (neat): υ
3142, 3084, 2962, 1726, 1608, 1562, 1433, 1302, 1248, 1195,
1
1186, 1101, 1049, 987 cmꢁ1; H-NMR (DMSO-d6, 400 MHz):
1
1195, 1111, 1049, 985 cmꢁ1; H-NMR (DMSO-d6, 400 MHz):
d 0.87 (t, 3H, J = 6.1 Hz), 1.19–1.23 (m, 2H), 1.75–1.80
(m, 2H), 2.76 (s, 3H), 4.34 (t, 2H, J = 6.1 Hz), 5.20 (s, 2H),
7.31 (t, 1H, J = 8.2 Hz), 7.41 (d, 1H, J = 7.2 Hz), 7.56–7.60
(m, 1H), 7.98 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.2,
19.4, 32.0, 49.8, 57.6, 109.2, 114.0, 117.0, 123.4, 124.8, 131.2,
134.8, 143.4, 155.7, 160.6, 162.3, 175.8; Mass (ES): m/z 393
[M + H]+, 415 [M + Na]+. Anal. Calcd. for C18H18ClFN4O3: C,
55.04; H, 4.62; N, 14.26%. Found: C, 54.86; H, 4.39, N, 14.29%.
d 0.87 (t, 3H, J = 5.6 Hz), 1.19–1.24 (m, 2H), 1.76–1.81
(m, 2H), 2.79 (s, 3H), 4.33 (t, 2H, J = 5.6 Hz), 5.21 (s, 2H),
7.49–7.54 (m, 3H), 7.82 (s, 1H). 13C-NMR (CDCl3, 100 MHz):
d 13.4, 19.6, 32.1, 49.9, 57.9, 109.1, 122.9, 127.6, 128.2,
130.8, 135.4, 142.1, 158.4, 160.8, 175.9; Mass (ES): m/z
409 [M + H]+, 432 [M + Na]+. Anal. Calcd. for C18H18Cl2N4O3:
C, 52.83; H, 4.43; N, 13.69%. Found: C, 52.83; H, 4.09; N, 13.86%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Synthesis of 1,2,3-Triazole Substituted Isoxazoles via Copper (I) Catalyzed Cycloaddition
627
(1-Allyl-1H-1,2,3-triazol-4-yl)methyl 3-(2-chloro-6-fluorophenyl)-
5-methylisoxazole-4 carboxylate (Vd5). Yield: 91%; IR (neat):
υ 3142, 3084, 2932, 1726, 1674, 1612, 1574, 1498, 1456,
Kyung, K. E.; Ae, K. E.; Seon, K. E.; Kyong, K. D.; Young-Ger, S.;
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Qing-Min, W. J Agric Food Chem 2010, 58, 2685; (c) Yu Han, Z.;
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ARKIVOC 2006, xvi, 35.
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Chandrashekar, S. M.; Kistayya, C. Eur J Med Chem 2010, 45, 2063;
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1
1388, 1304, 1251, 1143, 1099, 1051 cmꢁ1; H-NMR (DMSO-d6,
400 MHz): d 2.74 (s, 3H), 5.03 (d, 2H, J = 6.4 Hz), 5.18 (d, 1H,
J = 15.6 Hz), 5.20 (s, 2H), 5.29 (d, 1H, J = 9.1 Hz), 6.00–6.07
(m, 1H), 7.32 (t, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 7.8 Hz), 7.53–7.61
(m, 1H), 7.93 (s, 1H). 13C-NMR (CDCl3, 100 MHz): d 13.1,
52.4, 57.8, 109.3, 113.8, 117.5, 119.9, 123.1, 125.0, 131.2,
131.3, 135.0, 142.3, 155.2, 160.7, 162.4, 175.9; Mass (ES): m/z
377 [M + H]+, 399 [M + Na]+. Anal. Calcd. for C17H14ClFN4O3:
C, 54.19; H, 3.75; N, 14.87%. Found: C, 53.90; H, 3.75; N,
14.40%.
Acknowledgment. The author (P.V.R.) is thankful to the Head,
Department of Chemistry, and Director, Central Facility Building,
Osmania University, Hyderabad, for providing the spectral facility.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet