One-pot synthesis of 3,5-disubstituted isoxazoles from propargylic alcohols through propargylic N-hydroxylamines

Article abstract of DOI:10.1002/ejoc.201200628

An efficient approach has been described for the synthesis of 3,5-disubstituted isoxazoles from propargylic alcohols. The strategy involves a one-pot p-TSA-catalyzed N-propargylation of protected hydroxylamines followed by a TBAF-mediated detosylative 5-endo-dig cyclization. The method was successfully used for the synthesis of various 3,5-disubstituted isoxazoles.

Full text of DOI:10.1002/ejoc.201200628

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201200628
One-Pot Synthesis of 3,5-Disubstituted Isoxazoles from Propargylic Alcohols
through Propargylic N-Hydroxylamines
Chada Raji Reddy,*[a] Jonnalagadda Vijaykumar,[a] Enukonda Jithender,[a]
Gangireddy Pavan Kumar Reddy,[b] and René Grée[b]
Keywords: Synthetic methods / Nitrogen heterocycles / Alkylation / Propargylic alcohol / Isoxazole
An efficient approach has been described for the synthesis
of 3,5-disubstituted isoxazoles from propargylic alcohols. The
mediated detosylative 5-endo-dig cyclization. The method
was successfully used for the synthesis of various 3,5-disub-
stituted isoxazoles.
strategy involves
a one-pot p-TSA-catalyzed N-propar-
gylation of protected hydroxylamines followed by a TBAF-
amine and a 1,3-dicarbonyl compound/α,β-unsaturated
carbonyl compound.[4,5] However, thermal nitrile oxide–
alkyne cycloaddition reactions typically give relatively low
yields, side-reactions and poor regioselectivity. Further-
more, most of these methods require expensive metal cata-
lysts. Therefore, the regioselective synthesis of isoxazoles
under mild reaction conditions is useful.
Propargylic N-hydroxylamines represent a class of adapt-
able building blocks for the synthesis of various nitrogen-
containing heterocycles such as dihydroisoxazoles (Δ4-isox-
azolines), isoxazoles and acyl aziridines (Figure 2).[8] These
compounds are encountered as key intermediates in the
synthesis of several bioactive compounds.[9] Thus, these
compounds are interesting synthetic targets for chemists.
Usually, propargylic N-hydroxylamines are obtained
through a nucleophilic addition reaction of acetylides with
nitrones.[10] Recently, Campagne and co-workers developed
a FeCl3-catalyzed propargylic alcohol substitution reaction
by using N-protected hydroxylamine to afford propargylic
N-hydroxylamines, which were further converted into sub-
stituted isoxazoles or isoxazolines.[8b,8c,8e] Although, this is
Introduction
The isoxazole core is one of the important five-mem-
bered nitrogen heterocyclic motifs embedded in several nat-
ural products and drugs (Figure 1).[1] Among this prolific
family of heterocycles, 3,5-disubstituted isoxazoles attract
great interest owing to their wide range of applications in
medicinal chemistry.[2] Consequently, various strategies
have been developed to synthesize these valuable com-
pounds[3–7] and the majority of these methods are based on
either a [3+2] cycloaddition between an alkyne and nitrile
oxide[3] or a condensation reaction between a hydroxyl-
Figure 1. Representative examples of natural products and drugs
containing an isoxazole skeleton.
[a] Division of Natural Products Chemistry, CSIR – Indian Insti-
tute of Chemical Technology
Hyderabad 500607, India
Fax: +91-40-27160512
E-mail: rajireddy@iict.res.in
Homepage: www.iictindia.org
[b] Université de Rennes 1, Institut des Sciences Chimiques de
Rennes, CNRS UMR 6226,
Avenue du Général Leclerc, 35042 Rennes Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200628.
Figure 2. Synthesis of nitrogen-containing heterocycles from prop-
argylic N-hydroxylamine.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
C. Raji Reddy et al.
FULL PAPER
an attractive one-pot method, it requires a metal-catalyst Table 1. p-TSA-catalyzed N-propargylation of protected hydroxyl-
amines.[a]
for the nucleophilic substitution reaction (C–N bond for-
mation) and reflux temperatures for both the substitution
and the cyclization reactions. Meanwhile, we have devel-
oped an acid-catalyzed alkylation reaction using π-activated
alcohols as the alkylating agents.[11] Recently, O-proparg-
ylation of hydroximides in the presence of an organic acid
catalyst was accomplished,[12] which encouraged us to inves-
tigate the N-propargylation of protected hydroxylamines
under similar reaction conditions. Sanz and co-workers
have extensively studied p-TSA-catalyzed propargylic
alcohol substitution reactions by using different carbon,
oxygen, sulfur and nitrogen nucleophiles,[13] however there
is no example that uses a hydroxylamine. In this paper we
report the p-TSA-catalyzed N-propargylation of protected
hydroxylamines to give propargylic N-hydroxylamines and
application of this reaction as a one-pot synthesis for 3,5-
disubstituted isoxazoles (Scheme 1).
Scheme 1. Synthesis of propargylic N-hydroxylamines (3) and isox-
azoles (4).
[a] Conditions: alcohol (1 mmol), TsNHOH (1 mmol), p-TSA
1
(5 mol-%), CH2Cl2. [b] All the products were characterized by H,
13C NMR, and mass spectrometry. [c] Isolated yields.
Results and Discussion
propargylated products 3d and 3e in good yields (Table 2,
Initially, we attempted the N-propargylation of N-tosyl Entries 4 and 5). 1-(4-Methoxyphenyl)hex-2-yn-1-ol (1c)
hydroxylamine (2a) with propargylic alcohol 1a[14] in the also reacted with both 2a and 2b under p-TSA-catalyzed
presence of p-TSA (5 mol-%) in dichloromethane at room conditions to give corresponding propargylic N-hydroxyl-
temperature. The starting material was consumed in 20 min amines 3f and 3g in 98 and 95% yields, respectively
and desired N-propargylic hydroxylamine 3a was obtained (Table 1, Entries 6 and 7). In contrast, reaction of proparg-
in 88% yield (Table 1, Entry 1). The use of N-benzyloxy- ylic alcohol 1A with N-tosyl hydroxylamine failed to give
carbonyl hydroxylamine (2b) did not influence the efficiency the expected product even after 10 h at room temperature
of the propargylic hydroxy substitution reaction and N- or at 40 °C (Table 1, Entry 8). These results clearly demon-
propargylic hydroxylamine 3b was isolated in 81% yield strate that the N-propargylation of protected N-hydroxyl-
(Table 1, Entry 2). However, the use of N-tert-butyloxy-
carbonyl hydroxylamine (2c) gave a low yield of desired
product 3c (Table 1, Entry 3) possibly owing to the acid la-
bile nature of the di-tert-butyl dicarbonate (Boc) group. To
investigate the generality of the reaction, a diverse range of
substituted propargylic alcohols were considered as alkyl-
ating agents for N-propargylation of TsNHOH (2a) and
CbzNHOH (2b) under optimized conditions (Table 1).
Consequently, propargylic alcohols 1b and 1c were pre-
pared (Scheme 2) using a similar procedure for 1a and ex-
plored for their efficacy in the present reaction. Propargylic
alcohol 1b successfully reacted to give the corresponding N- Scheme 2. Synthesis of propargylic alcohols 1b to 1k.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
One-Pot Synthesis of 3,5-Disubstituted Isoxazoles
amines is successful only with propargyl alcohols generated ence of p-TSA (5 mol-%) followed by TBAF-mediated deto-
from aromatic aldehydes and not with those generated from sylative 5-endo-dig cyclization to afford corresponding isox-
aliphatic aldehydes.
azoles 4g to 4j in good yields (Table 3, Entries 7–10). Like-
wise, propargylic alcohol 1k (Scheme 2) afforded desilylated
isoxazole 4k in 88% yield (Table 3, Entry 11). During the
TBAF-mediated cyclization step, deprotection of the tert-
butyldiphenyl silyl group also occurred to furnish 4g–4k
with a free hydroxy group, which is a useful functionality
for further derivatization of these isoxazoles.
Table 2. Conversion of N-propargylic hydroxylamine 3a to isox-
azole 4a.
Table 3. One-pot synthesis of isoxazoles from propargylic
alcohols.[a]
[a] Isolated yield after purification.
Next, our attention turned to the conversion of proparg-
ylic N-hydroxylamines (3) to isoxazoles (4) through detos-
ylative 5-endo-dig-cyclization. To identify suitable reaction
conditions, 3a was treated with different bases to obtain
corresponding isoxazole 4a (Table 2). The reaction of 3a
with K2CO3 provided desired isoxazole 4a in 58% yield in
20 h along with a mixture of unidentified products (Table 2,
Entry 1), and treatment with CsF gave a similar result in
12 h providing 4a in 36% yield (Table 2, Entry 2). Interest-
ingly, tetrabutylammonium fluoride (TBAF) was more ef-
fective giving 4a in 86% yield at room temperature (Table 2,
Entry 3) and these conditions are mild relative to those de-
scribed in a literature method (Et3N, CH2Cl2, reflux).[8c] To
the best of our knowledge, there is no literature precedence
on TBAF-mediated cyclization reactions for the synthesis
of substituted isoxazoles.
Having defined the mild reaction conditions for the syn-
thesis of propargylic N-hydroxylamines and their conver-
sion to 3,5-disubstituted isoxazoles, we were interested in
developing a one-pot reaction. Reaction of propargylic
alcohol 1a with N-tosyl hydroxylamine (2a) in the presence
of p-TSA (5 mol-%) in dichloromethane for 30 min, fol-
lowed by the addition of TBAF resulted in the clean forma-
tion of 3,5-diphenyl isoxazole (4a) in 82% yield (Table 3,
Entry 1). The above success encouraged us to extend this
one-pot method to the synthesis of 3,5-disubstituted isox-
azoles (Table 3) from diverse propargylic alcohols, which
were prepared as shown in Scheme 2. Propargylic alcohol
1b (bearing an aryl group on the alkyne), 1c and 1d (with
alkyl substitution on the alkyne) afforded the correspond-
ing 3,5-disubstituted isoxazoles 4b to 4d, respectively, under
one-pot reaction conditions (Table 3, Entries 2–4).[15]
Alcohols 1e and 1f, generated from benzyloxy prop-2-yne,
were also suitable for this one-pot protocol and gave desired
isoxazoles 4e and 4f (Table 3, Entries 5 and 6). Propargylic
alcohols 1g to 1j, derived from tert-butyldiphenyl silyloxy
[a] Conditions: alcohol (1 mmol), TsNHOH (1 mmol), p-TSA
(5 mol-%), CH2Cl2 then TBAF (3 mmol). [b] All the products were
1
prop-2-yne, reacted smoothly with TsNHOH in the pres- characterized by H, 13C NMR, and mass spectra; isolated yields.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
C. Raji Reddy et al.
FULL PAPER
drous Na2SO4, concentrated in vacuo and purified by column
chromatography (silica gel) to afford pure propargylic alcohols 1b
to 1k.
To investigate the mechanism of the substitution reaction,
an enantio-enriched propargylic alcohol 1d (30% ee)[16a]
was treated with TsNHOH and p-TSA (5 mol-%) in CH2Cl2
and product 3h was obtained in 82% yield in racemic form. The spectroscopic data of 1b to 1f were in full agreement with the
literature data.[18]
Similarly, reaction of alcohol 1e (82% ee)[16b] also provided
racemic N-hydroxylamine 3i (Scheme 3). These results
strongly suggest that the nucleophilic substitution reaction
proceeds through a SN1 mechanism.
4-(tert-Butyldiphenylsilyloxy)-1-phenylbut-2-yn-1-ol (1g): Viscous li-
quid. IR (KBr): ν = 3379, 2931, 1428, 1371, 1111, 1081, 739,
˜
701 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.75–7.69 (m, 4 H,
Ar), 7.49–7.30 (m, 11 H, Ar), 5.38 (br. s, 1 H, CH–OH), 4.44–
4.41 (m, 2 H, CH2–OTBDPS), 1.06 (s, 9 H, tBu) ppm. 13C NMR
(75 MHz, CDCl3): δ = 140.3, 135.6, 133.0, 129.7, 128.4, 128.1,
127.6, 126.5, 84.9, 84.8, 64.4, 52.6, 26.6, 19.0 ppm. HRMS (ESI):
calcd. for C26H28NaO2Si [M + Na]+ 423.1751; found 423.1730.
4-(tert-Butyldiphenylsilyloxy)-1-(2,3-dimethoxyphenyl)but-2-yn-
1-ol (1h): Viscous liquid. IR (KBr): ν = 3443, 2937, 1589, 1480,
˜
1
1271, 1076, 704 cm–1. H NMR (300 MHz, CDCl3): δ = 7.72–7.66
(m, 4 H, Ar), 7.43–7.31 (m, 6 H, Ar), 7.08–6.98 (m, 2 H, Ar), 6.91
(dd, J = 2.2, 7.5 Hz, 1 H, Ar), 5.55 (br. s, 1 H, CH–OH), 4.38 (d,
J = 1.5 Hz, 2 H, CH2–OTBDPS), 3.90 (s, 3 H, OCH3), 3.87 (s, 3
H, OCH3) 2.96–2.90 (br. s, 1 H, OH), 1.03 (s, 9 H, tBu) ppm. 13C
NMR (75 MHz, CDCl3): δ = 152.5, 146.5, 135.5, 129.7, 127.6,
124.1, 119.5, 112.6, 85.2, 84.1, 61.2, 61.0, 55.8, 52.7, 26.6,
19.0 ppm. HRMS (ESI): calcd. for C28H32NaO4Si [M + Na]+
483.1962; found 483.1965.
Scheme 3. N-Propargylation with enantio-enriched alcohols 1d and
1e.
Conclusions
In conclusion, we have developed a p-TSA-catalyzed re-
action (C–N bond formation) between propargylic alcohols
and N-protected hydroxylamines to give propargylic N-hy-
droxylamines, which are useful precursors for various nitro-
gen-containing heterocycles. This method was extended to a
one-pot synthesis of isoxazoles through a TBAF-mediated
detosylative 5-endo-dig cyclization. The present method is
short (a total of 2 steps) and flexible because it starts from
three simple components (an aromatic aldehyde, an alkyne
and tosylhydroxylamine). This mild and metal-free reaction
makes it practical as an organic synthetic method to obtain
3,5-disubstituted isoxazoles.
4-(tert-Butyldiphenylsilyloxy)-1-(3-methyl-1-phenyl-1H-pyrazol-4-
yl)but-2-yn-1-ol (1i): Viscous liquid. IR (KBr): ν = 3343, 2957,
˜
1
2858, 1597, 1503, 1112, 1000, 757, 704 cm–1. H NMR (300 MHz,
CDCl3): δ = 7.82 (s, 1 H, =CH–N), 7.75–7.69 (m, 5 H, Ar), 7.59
(d, J = 8.3 Hz, 2 H, Ar), 7.43–7.35 (m, 8 H, Ar), 5.39 (br. s, 1 H,
CH–OH), 4.44 (d, J = 1.5 Hz, 2 H, CH2–OTBDPS), 2.37 (s, 3 H,
CH3), 1.06 (s, 9 H, tBu) ppm. 13C NMR (75 MHz, CDCl3): δ =
148.5, 139.8, 135.5, 133.0, 129.8, 129.2, 127.6, 126.3, 126.0, 121.8,
119.5, 118.7, 84.5, 83.4, 56.3, 52.6, 26.6, 19.1, 12.1 ppm. HRMS
(ESI): calcd. for C31H33O3Si [M + H]+ 481.2193; found 481.2220.
4-(tert-Butyldiphenylsilyloxy)-1-(thiophen-2-yl)but-2-yn-1-ol (1j):
Viscous liquid. IR (KBr): ν = 3447, 2930, 2858, 1428, 1369, 1111,
˜
703 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.75–7.70 (m, 4 H,
Ar), 7.46–7.35 (m, 6 H, Ar), 7.28 (d, J = 4.4 Hz 1 H, Ar), 7.08 (s,
1 H, Ar), 6.97–6.94 (m, 1 H, Ar), 5.59 (s, 1 H, CH–C), 4.44 (s, 2
H, CH2–OTBDPS), 2.13 (br. s, 1 H, OH), 1.07 (s, 9 H, tBu) ppm.
13C NMR (75 MHz, CDCl3): δ = 141.4, 135.5, 132.8, 129.8, 127.7,
127.0, 126.6, 126.3, 126.2, 86.1, 81.8, 64.8, 52.7, 26.6, 19.1 ppm.
Experimental Section
General: NMR spectra were recorded in CDCl3 with 300, 400 and
500 MHz spectrometers at ambient temperature. The chemical
shifts (δ) are reported relative to TMS as the internal standard and
by using the signal patterns indicated as follows: s, singlet; d, doub-
let; dd, doublet of doublets; td, triplet of doublets; t, triplet; m,
multiplet; br. s, broad singlet. All the reagents and solvents were
reagent grade and were used without further purification. Technical
grade ethyl acetate and petroleum ether used for column
chromatography were distilled prior to use. Column chromatog-
raphy was carried out using silica gel (60–120 mesh) packed in glass
columns. All the reactions were performed under an atmosphere of
nitrogen in flame- or oven-dried glassware with magnetic stirring.
Propargylic alcohol 1a was prepared as described.[14] TsNHOH was
prepared using the literature procedure.[17]
1-{4-[(tert-Butyldiphenylsilyloxy)methyl]phenyl}-3-[4-(pentyloxy)-
phenyl]prop-2-yn-1-ol (1k): Viscous liquid. IR (KBr): ν = 3409,
˜
2933, 2192, 1604, 1509, 1288, 1248, 1109 cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 7.73–7.67 (m, 5 H, Ar), 7.59 (d, J = 8.1 Hz,
2 H, Ar), 7.44–7.36 (m, 9 H, Ar), 6.86–6.81 (m, 2 H, Ar), 5.68 (s,
1 H, CH–OH), 4.79 (s, 2 H, CH2–OTBDPS), 3.95 (t, J = 6.6 Hz,
2 H, Ar–OCH2), 1.83–1.74 (m, 2 H, CH2), 1.49–1.33 (m, 4 H, CH2–
CH2), 1.10 (s, 9 H, tBu), 0.93 (t, J = 6.9 Hz, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.3, 141.2, 139.4, 135.4, 135.1,
133.1, 129.8, 129.6, 129.5, 127.7, 127.6, 126.6, 126.1, 125.7, 114.8,
114.3, 87.3, 86.6, 67.9, 65.1, 64.9, 28.8, 28.0, 26.7, 22.3, 19.2,
13.9 ppm. HRMS (ESI): calcd. for C37H42NaO3Si [M + Na]+
585.2795; found 585.2801.
General Procedure for the Synthesis of 1b to 1k: The starting alkyne
(1.1 mmol) was dissolved in dry THF (5 mL) and n-BuLi (1 mmol)
was added slowly at –78 °C. After 40 min the appropriate aromatic
aldehyde (1 mmol) in THF (5 mL) was added to the reaction mix-
ture at –78 °C. The reaction mixture was stirred at –78 °C until the
aldehyde had been consumed, then quenched by adding aq. satu-
rated NH4Cl solution and was extracted with ethyl acetate
(2ϫ15 mL). The combined organic layers were dried with anhy-
General Procedure for the Preparation of Propargylic N-Hydroxyl-
amines: p-TSA (5 mol-%) was added to a mixture of propargylic
alcohols 1a–1c (1.0 mmol) and N-protected hydroxylamine 2a–2c
(1.0 mmol) in dichloromethane (5 mL) at room temperature and
stirred (for times, see: Table 1). The mixture was diluted with H2O
(10 mL) and extracted with CH2Cl2 (2ϫ15 mL). The combined or-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
One-Pot Synthesis of 3,5-Disubstituted Isoxazoles
ganic layers were dried with anhydrous Na2SO4, concentrated in
vacuo and purified by column chromatography to afford N-prop-
argylated hydroxylamines 3a to 3g.
NMR (75 MHz, CDCl3): δ = 159.4, 144.4, 132.1, 129.9, 129.5,
129.0, 128.6, 113.6, 89.6, 72.3, 56.2, 55.3, 21.6, 21.5, 20.5,
13.4 ppm. HRMS (ESI): calcd. for C20H23NNaO4S [M + Na]+
396.124; found 396.122.
N-(1,3-Diphenylprop-2-ynyl)-N-hydroxy-4-methylbenzenesulfon-
amide (3a): White solid; m.p. 126–129 °C. IR (KBr): ν = 3369,
Benzyl Hydroxy[1-(4-methoxyphenyl)hex-2-ynyl]carbamate (3g):
˜
3032, 2228, 1491, 1452, 1166, 1089, 758, 670 cm–1
.
1H NMR Colorless liquid. IR (KBr): ν = 3308, 3034, 2218, 1704, 1457, 754,
˜
1
(300 MHz, CDCl3): δ = 7.91 (d, J = 8.3 Hz, 2 H, Ar), 7.63 (d, J =
6.4 Hz, 2 H, Ar), 7.41–7.15 (m, 8 H, Ar), 7.05 (d, J = 6.4 Hz, 2 H,
696 cm–1. H NMR (300 MHz, CDCl3): δ = 7.44 (d, J = 8.3 Hz, 2
H, Ar), 7.40–7.32 (m, 5 H, Ar), 6.85 (d, J = 8.3 Hz, 2 H, Ar), 6.07
Ar), 5.99 (s, 1 H, CH–N), 2.22 (s, 3 H, CH3) ppm. 13C NMR (t, J = 1.5 Hz, 1 H, CH–N), 5.23 (d, J = 2.2 Hz, 2 H, PhCH2), 3.79
(75 MHz, CDCl3): δ = 144.9, 136.0, 131.6, 129.8, 129.2, 128.5, (s, 3 H, OCH3), 2.25 (td, J = 2.2, 7.5 Hz, 2 H, C–CH2), 1.61–1.53
128.4, 127.9, 122.0, 88.8, 81.3, 57.1, 21.4 ppm. HRMS (ESI): calcd.
(m, 2 H, CH3CH2), 1.00 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 159.3, 157.0, 135.6, 129.2, 128.8,
128.5, 128.4, 128.2, 128.0, 113.5, 86.8, 75.2, 68.1, 55.1, 55.0, 21.9,
20.6, 13.4 ppm. HRMS (ESI): calcd. for C20H23NNaO4S [M +
Na]+ 376.0978; found 376.0909.
for C22H19NNaO3S [M + Na]+ 400.0978; found 400.0996.
Benzyl 1,3-Diphenylprop-2-ynyl(hydroxy)carbamate (3b): White so-
lid; m.p. 116–118 °C. IR (KBr): ν = 3301, 3034, 2222, 1705, 1491,
˜
1
1450, 1408, 756, 694 cm–1. H NMR (300 MHz, CDCl3): δ = 7.57
(d, J = 6.4 Hz, 2 H, Ar), 7.50–7.42 (m, 2 H, Ar), 7.39–7.25 (s, 11
N-Hydroxy-4-methyl-N-(1-phenylnon-2-ynyl)benzenesulfonamide
H, Ar), 6.30 (s, 1 H, CH–N), 5.23 (s, 2 H, PhCH2), 4.10 (br. s, 1 (3h): Colorless liquid. IR (KBr): ν = 2925, 2855, 1689, 1454, 1376,
˜
H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 157.0, 135.8, 135.5,
131.9, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 128.0, 122.2, 86.4,
1173 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.91–7.87 (d, 2 H,
Ar), 7.58–7.53 (m, 2 H, Ar), 7.37–7.28 (m, 5 H, Ar), 5.79 (t, J =
84.0, 68.4, 56.0 ppm. HRMS (ESI): calcd. for C23H20NO3 [M + 2.2 Hz, 1 H, CH–N), 2.45 (s, 3 H, CH3–SO2), 1.86–1.80 (m, 2 H,
H]+ 358.1438; found 358.1453.
OCH2), 1.31–1.19 (m, 8 H, aliphatic), 0.88 (t, J = 7.5 Hz, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4, 136.4, 132.0,
129.9, 129.0, 128.3, 128.2, 90.9, 71.9, 56.7, 31.2, 28.5, 28.1, 22.4,
21.6, 18.5, 13.9 ppm. HRMS (ESI): calcd. for C22H27NO3SNa
408.1609 [M + Na]+; found 408.1610; HPLC (Chiral pack IC
250 ϫ 4.6 mm, 5 μ, 4 % 2-propanol in hexanes, flow rate =
1 mLmin–1): tR = 15.25 (50.08%), 20.57 (49.91%) min.
tert-Butyl 1,3-Diphenylprop-2-ynyl(hydroxy)carbamate (3c): White
solid; m.p. 120–123 °C. IR (KBr): ν = 3357, 3031, 2227, 1650, 1490,
˜
1425, 759 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.64 (d, J =
6.6 Hz, 2 H, Ar), 7.54–7.48 (m, 2 H, Ar), 7.44–7.30 (m, 6 H, Ar),
6.24 (s, 1 H, OH), 5.89 (s, 1 H, CH–N), 1.54 (s, 9 H, tBu) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.8, 136.1, 131.8, 128.5, 128.4,
128.2, 127.9, 122.3, 86.1, 84.2, 83.0, 56.3, 28.2 ppm. HRMS (ESI):
calcd. For C20H21NNaO3 [M + Na]+ 346.1414; found 346.1415.
N-[4-(Benzyloxy)-1-phenylbut-2-ynyl]-N-hydroxy-4-methylbenz-
enesulfonamide (3i): Colorless liquid. IR (KBr): ν = 3238, 1452,
˜
1
1343, 1165, 770 cm–1. H NMR (300 MHz, CDCl3): δ = 7.90 (d, J
N-Hydroxy-4-methyl-N-[3-phenyl-1-(1-tosyl-1H-indol-3-yl)prop-
= 7.7 Hz, 1 H, Ar), 7.84 (d, J = 7.7 Hz, 2 H, Ar), 7.59–7.53 (m, 2
H, Ar), 7.40–7.26 (m, 10 H, Ar), 6.72 (s, 1 H, OH), 6.30 (s, 1 H,
CH–N), 4.64–4.59 (m, 1 H, Ph–CH2), 4.45–4.39 (m, 1 H, Ph–CH2),
4.27 (s, 1 H, O–CH2), 3.83 (s, 1 H, O–CH2), 2.46 (s, 3 H,
SO2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.8, 143.2,
136.1, 133.9, 129.3, 128.7, 128.4, 128.1, 128.0, 127.8, 127.5, 127.4,
127.2, 126.1, 83.9, 79.1, 70.6, 56.4, 56.2, 21.0 ppm. MS (ESI): m/z
= 444 [M + Na]+. HPLC (Chiral pack IC 250ϫ4.6 mm, 5 μ, 10%
2-propanol in hexanes, flow rate = 1 mL min–1): tR = 9.63
(50.48%), 10.42 (49.52%) min.
2-ynyl]benzenesulfonamide (3d): White solid; m.p. 155–158 °C. IR
1
(KBr): ν = 2912, 1593, 1446, 1164, 1098, 770, 673 cm–1. H NMR
˜
(300 MHz, CDCl3 + DMSO): δ = 7.96 (d, J = 8.1 Hz, 1 H, Ar),
7.87 (d, J = 8.1 Hz, 3 H, Ar), 7.75 (d, J = 8.1 Hz, 3 H, Ar), 7.40–
7.16 (m, 10 H, Ar, & CH=C), 7.08 (d, J = 6.4 Hz, 1 H, Ar), 6.21
(s, 1 H, CH–N), 2.33 (s, 3 H, CH3–N), 2.24 (s, 3 H, CH3–N–
Ar) ppm. 13C NMR (75 MHz, CDCl3 + DMSO): δ = 144.7, 144.3,
134.8, 134.7, 131.7, 131.3, 129.7, 129.5, 128.8, 128.4, 128.0, 127.6,
126.6, 126.3, 124.6, 123.0, 121.7, 120.3, 118.4, 113.1, 86.4, 81.1,
50.2, 21.2, 21.1 ppm. HRMS (ESI): calcd. for C31H26N2NaO5S2
[M + Na]+ 593.1175; found 593.1199.
Synthesis of Isoxazole 4a from 3a: TBAF (1 m in THF, 3.0 mmol)
was added to a solution of N-propargylated hydroxylamine (3a,
1.0 mmol) in dichloromethane (5 mL) at 0 °C. The reaction mixture
was stirred at room temperature for 10 min. The mixture was
quenched by adding saturated NH4Cl solution and was extracted
with CH2Cl2 (2ϫ15 mL). The combined organic layers were dried
with anhydrous Na2SO4, concentrated in vacuo and purified by
column chromatography (silica gel) to afford pure 4a.
Benzyl Hydroxy[3-phenyl-1-(1-tosyl-1H-indol-3-yl)prop-2-ynyl]-
carbamate (3e): Colorless liquid. IR (KBr): ν = 2923, 2197, 1705,
˜
1596, 1490, 1446, 1174, 754, 675 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.95 (d, J = 8.3 Hz, 1 H, Ar), 7.85 (s, 1 H, CH=C),
7.77 (d, J = 8.3 Hz, 2 H, Ar), 7.61 (d, J = 7.4 Hz, 1 H, Ar), 7.50
(d, J = 6.5 Hz, 2 H, Ar), 7.42–7.28 (m, 9 H, Ar), 7.21 (d, J =
8.3 Hz, 3 H, Ar), 6.51 (s, 1 H, CH–N), 6.05–5.95 (m, 1 H, OH),
5.25 (s, 2 H, Ph–CH2), 2.32 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, 3,5-Diphenylisoxazole (4a):[8c] White solid; m.p. 135–138 °C. IR
CDCl3): δ = 156.8, 144.9, 135.3, 135.1, 134.8, 131.8, 129.7, 128.6,
128.4, 128.1, 128.0, 126.7, 126.5, 124.8, 123.2, 121.9, 120.0, 117.9,
113.4, 85.2, 83.3, 68.3, 48.9, 21.3 ppm. HRMS (ESI): calcd. for
C32H26N2NaO5S [M + Na]+ 573.1455; found 573.1471.
(KBr): ν = 3110, 3044, 2924, 1612, 1568, 1485, 1453, 1259, 1073,
˜
1
762, 689 cm–1. H NMR (300 MHz, CDCl3): δ = 7.91–7.82 (m, 4
H, Ar), 7.54–7.44 (m, 6 H, Ar), 6.84 (s, 1 H, CH=C) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.4, 162.9, 130.2, 129.9, 129.1,
129.0, 128.9, 127.4, 126.8, 125.8, 97.4 ppm. HRMS (ESI): calcd.
for C15H12NO [M + H]+ 222.0913; found 222.0919.
N-Hydroxy-N-[1-(4-methoxyphenyl)hex-2-ynyl]-4-methylbenzene-
sulfonamide (3f): White solid; m.p. 103–105 °C. IR (KBr): ν = 3339,
˜
2962, 1743, 1604, 1458, 809, 668 cm–1 1H NMR (300 MHz, General Procedure for One-Pot Synthesis of Isoxazoles 4a to 4k
.
CDCl3): δ = 7.89 (d, J = 8.3 Hz, 2 H, Ar), 7.46 (d, J = 9.0 Hz, 2
H, Ar), 7.34 (d, J = 7.5 Hz, 2 H, Ar), 6.85 (d, J = 8.3 Hz, 2 H,
Ar), 5.77 (t, J = 2.2 Hz, 1 H, CH–N), 3.79 (s, 3 H, OCH3), 2.45 (s,
from Propargylic Alcohols: p-TSA (5 mol-%) was added to a mix-
ture of propargylic alcohol 1a–h (1.0 mmol) and tosyl hydroxyl-
amine 2a (1.0 mmol) in dichloromethane (5 mL) at room tempera-
3 H, Ts–CH3), 1.84 (td, J = 2.2, 6.7 Hz, 2 H, C–CH2), 1.36–1.23 ture, and stirred (for times, see Table 1). Next, TBAF (1 m in THF,
(m, 2 H, CH3CH2), 0.85 (t, J = 7.5 Hz, 3 H, CH2CH3) ppm. 13C 3.0 mmol) was added at 0 °C and stirred at room temperature until
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
C. Raji Reddy et al.
FULL PAPER
complete consumption of the starting material (for times, see
Table 2). The mixture was quenched by adding saturated NH4Cl
solution and was extracted with CH2Cl2 (2ϫ15 mL). The com-
bined organic layers were dried with anhydrous Na2SO4, concen-
trated in vacuo and purified by column chromatography (silica gel)
to afford the 3,5-disubstituted isoxazoles 4a–h.
120.7, 113.7, 102.9, 60.8, 56.3, 55.8 ppm. HRMS (ESI): calcd. for
C12H14NO4 [M + H]+ 236.0917; found 236.0909.
[3-(3-Methyl-1-phenyl-1H-pyrazol-4-yl)isoxazol-5-yl]methanol (4i):
Viscous liquid. IR (KBr): ν = 3359, 2923, 1513, 1458, 1368, 1161,
˜
757 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.19 (s, 1 H, =CH–
NPh), 7.66 (d, J = 7.5 Hz, 2 H, Ar), 7.44 (t, J = 7.5 Hz, 2 H, Ar),
7.29 (t, J = 7.5 Hz, 1 H, Ar), 6.41 (s, 1 H, CH=C–O), 4.78 (s, 2 H,
CH2OH), 2.54 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 171.4, 156.0, 149.0, 139.4, 129.4, 126.7, 119.0, 111.3, 100.5, 56.4,
5-Phenyl-3-(1-tosyl-1H-indol-3-yl)isoxazole (4b): Viscous liquid. IR
1
(KBr): ν = 3119, 1619, 1490, 1439, 1133, 762, 657 cm–1. H NMR
˜
(300 MHz, CDCl3): δ = 8.28–8.23 (m, 1 H, Ar), 8.06–8.00 (m, 2 H,
Ar), 7.89–7.80 (m, 4 H, Ar), 7.55–7.33 (m, 5 H, Ar), 7.29–7.22 (m,
2 H, Ar), 6.84 (s, 1 H, CH=C–Ph), 2.37 (s, 3 H, CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 169.6, 157.3, 145.4, 135.2, 134.8,
130.3, 130.0, 129.0, 127.7, 127.2, 126.9, 125.8, 125.7, 125.5, 124.1,
122.6, 113.4, 112.4, 97.7, 21.5 ppm. HRMS (ESI): calcd. for
C24H19N2O3S [M + H]+ 415.1111; found 415.1076.
13.7 ppm. HRMS (ESI): calcd. for C14H14N3O2 [M
256.1081; found 256.1059.
+
H]+
[3-(Thiophen-2-yl)isoxazol-5-yl]methanol (4j): Viscous liquid. IR
(KBr): ν = 3375, 2925, 1604, 1551, 1464, 1156, 709 cm–1. 1H NMR
˜
(300 MHz, CDCl3): δ = 7.45–7.39 (m, 2 H, Ar), 7.11 (q, J = 3.7 Hz,
1 H, Ar), 6.49 (s, 1 H, CH=C–O), 4.79 (s, 2 H, CH2OH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 171.9, 157.6, 130.4, 127.7, 127.6,
127.5, 100.0, 56.4 ppm.
3-(4-Methoxyphenyl)-5-propylisoxazole (4c): Viscous liquid. IR
(KBr): ν = 2963, 1610, 1577, 1528, 1461, 1178, 793 cm–1. 1H NMR
˜
(500 MHz, CDCl3): δ = 7.70 (d, J = 7.9 Hz, 2 H, Ar), 6.94 (d, J =
8.9 Hz, 2 H, Ar), 6.20 (s, 1 H, CH=C–O), 3.85 (s, 3 H, OCH3),
2.76 (t, J = 7.9 Hz, 2 H, =C–CH2), 1.84–1.75 (m, 2 H, CH3–CH2),
1.04 (t, J = 7.9 Hz, 3 H, CH3–CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.7, 161.8, 160.7, 128.0, 121.9, 114.1, 98.5, 55.2,
28.6, 20.8, 13.6 ppm. HRMS (ESI): calcd. for C13H16NO2
[M + H]+ 218.1176; found 218.1174.
(4-{5-[4-(Pentyloxy)phenyl]isoxazol-3-yl}phenyl)methanol (4k): Vis-
cous liquid. IR (KBr): ν = 3402, 2932, 1601, 1508, 1256, 1171,
˜
1020, 808 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.86 (d, J =
7.9 Hz, 2 H, Ar), 7.76 (d, J = 8.9 Hz, 2 H, Ar), 7.48 (d, J = 7.9 Hz,
2 H, Ar), 6.98 (d, J = 8.9 Hz, 2 H, Ar), 6.69 (s, 1 H, CH–C–O),
4.77 (s, 2 H, CH2–OH), 4.02 (t, J = 6.9 Hz, 2 H, Ar–OCH2), 1.85–
1.79 (m, 2 H, CH2), 1.49–1.38 (m, 4 H, CH2–CH2), 0.95 (t, J =
6.9 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.6,
160.7, 142.6, 135.5, 127.3, 127.2, 126.9, 114.8, 95.9, 68.1, 64.9, 28.8,
28.1, 22.4, 14.0 ppm. HRMS (ESI): calcd. for C21H24NO3
[M + H]+ 338.1751; found 338.1740.
5-Hexyl-3-phenylisoxazole (4d): Viscous liquid. IR (KBr): ν = 3109,
˜
1
1614, 1563, 1456, 1169, 774 cm–1. H NMR (300 MHz, CDCl3): δ
= 7.83–7.75 (m, 2 H), 7.49–7.39 (m, 3 H), 6.28 (s, 1 H), 2.78 (t, J
= 7.4 Hz, 2 H), 1.80–1.62 (m, 2 H), 1.46–1.25 (m, 6 H), 0.9 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.2, 162.2,
129.7, 128.8, 126.7, 98.7, 31.4, 28.7, 27.5, 26.8, 22.5, 14.0 ppm.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all new compounds.
5-(Benzyloxymethyl)-3-phenylisoxazole (4e): Viscous liquid. IR
(KBr): ν = 3032, 1607, 1577, 1445, 1169, 771 cm–1 1H NMR
.
˜
Acknowledgments
(500 MHz, CDCl3): δ = 7.82 (d, J = 5.8 Hz, 2 H, Ar), 7.46 (d, J =
5.8 Hz, 3 H, Ar), 7.41–7.33 (m, 5 H, Ar), 6.59 (s, 1 H, CH=C–O),
4.68 (s, 2 H, CH2–OBn), 4.66 (s, 2 H, OCH2Ph) ppm. 13C NMR
(75 MHz, CDCl3): δ = 169.8, 162.3, 137.0, 129.9, 128.8, 128.4,
128.3, 128.2, 127.9, 127.8, 127.7, 127.4, 126.7, 100.9, 72.9,
62.7 ppm. HRMS (ESI): calcd. for C17H16NO2 [M + H]+ 266.1176;
found 266.1153.
J. V. thanks the Department of Science and Technology (DST),
New Delhi and E. J. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for research fellowships. This work
has been carried out as part of the Indo-French Joint Laboratory
for Sustainable Chemistry at Interfaces. The authors thank CSIR,
the Centre National de la Recherche Scientifique (CNRS), the Uni-
versity of Rennes 1 and IFCPAR/CEFIPRA for support.
5-(Benzyloxymethyl)-3-(4-methoxyphenyl)isoxazole (4f): Viscous li-
quid. IR (KBr): ν = 2923, 1611, 1528, 1456, 1177, 740, 699 cm–1.
˜
1H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 8.7 Hz, 2 H, Ar),
7.39–7.30 (m, 5 H, Ar), 6.97 (d, J = 8.7 Hz, 2 H, Ar), 6.52 (s, 1 H,
CH=C–O), 4.65 (s, 2 H, =C–CH2), 4.64 (s, 2 H, OCH2Ph), 3.85 (s,
3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.5, 161.9,
160.9, 137.1, 130.2, 128.5, 128.1, 128.0, 127.9, 121.4, 114.2, 100.8,
72.9, 62.8, 55.3 ppm. HRMS (ESI): calcd. for C18H18NO3 [M +
H]+ 296.1281; found 296.1249.
[1] a) D. Giomi, F. M. Cordero, F. Machetti, in: Comprehensive
Heterocyclic Chemistry III (Eds.: A. R. Katriski, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor, J. Joule), Elsevier,
Oxford, U. K., 2008, vol. 4, p. 365–486; b) M. Sutharchanad-
evi, in: Comprehensive Heterocyclic Chemistry II (Eds.: A. R.
Katriski, A. R. Rees, E. F. V. Scriven, I. Shinkai), Elsevier, Ox-
ford, U. K., 1996, vol. 3, p. 221–260; c) L. Carlsen, D. Döpp,
H. Döpp, F. Duus, H. Hartmann, S. Lang-Fugmann, B.
Schulze, R. K. Smalley, B. J. Wakefield, in: Houben–Weyl,
Methods in Organic Chemistry (Ed.: E. Ed. Schaumann), Thi-
eme, Stuttgart, Germany, 1992, vol. E8a, p. 45–204; d) F.
Behrens, M. Koehm, H. Burkhardt, Curr. Opin. Rheumatol.
2011, 23, 282–287; e) J. Sperry, D. Wright, Curr. Opin. Drug
Discov. Devel. 2005, 8, 723–740; f) K. D. Shin, M.-Y. Lee, D.-
S. Shin, S. Lee, K.-H. Son, S. Koh, Y.-K. Paik, B.-M. Kwon,
D. C. Han, J. Biol. Chem. 2005, 280, 41439–41448.
(3-Phenylisoxazol-5-yl)methanol (4g):[19] Viscous liquid. IR (KBr):
ν = 3368, 2924, 1607, 1445, 1406, 1168, 1037, 768, 693 cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H, Ar), 7.48–7.43
(m, 3 H, Ar), 6.57 (s, 1 H, CH=C–O), 4.82 (s, 2 H, CH2–OH) ppm.
13C NMR (75 MHz, CDCl3): δ = 172.1, 162.3, 130.0, 128.8,128.6,
126.7, 99.9, 56.2 ppm.
5-(Benzyloxymethyl)-3-(2,3-dimethoxyphenyl)isoxazole (4h): Vis-
cous liquid. IR (KBr): ν = 3393, 2934, 1604, 1579, 1483, 1453,
˜
[2] a) M. Koufaki, A. Tsatsaroni, X. Alexi, H. Guerrand, S. Zerva,
M. N. Alexis, Bioorg. Med. Chem. 2011, 19, 4841–4850; b) Y.
Fall, C. Reynaud, H. Doucet, M. Santelli, Eur. J. Org. Chem.
2009, 4041–4050; c) D. A. Patrick, S. A. Bakunov, S. M. Baku-
nova, E. V. K. S. Kumar, R. J. Lombardy, S. K. Jones, A. S.
Bridges, O. Zhirnov, J. E. Hall, T. Wenzler, R. Brun, R. R.
1103, 789 cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.41 (dd, J =
1.3, 7.9 Hz, 1 H, Ar), 7.13 (t, J = 8.1 Hz, 1 H, Ar), 7.00 (dd, J =
1.1, 8.1 Hz, 1 H, Ar), 6.75 (s, 1 H, CH=C–O), 4.81 (s, 2 H,
CH2OH), 3.90 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 171.2, 159.8, 153.1, 147.3, 124.4, 123.0,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
One-Pot Synthesis of 3,5-Disubstituted Isoxazoles
Tidwell, J. Med. Chem. 2007, 50, 2468–2485; d) R. Epple, M.
Azimioara, R. Russo, Y. Xie, X. Wang, C. Cow, J. Wityak, D.
Karanewsky, B. Bursulaya, A. Kreusch, T. Tuntland, A.
Gerken, M. Iskandar, E. Saez, H. M. Seidel, S.-S. Tianc, Bi-
oorg. Med. Chem. Lett. 2006, 16, 5488–5492.
X. Luo, J. Am. Chem. Soc. 2002, 124, 4716–4721; d) D. A.
Dickman, Y.-Y. Ku, H. Y. Morton, S. R. Chemburkar, H. H.
Patel, A. Thomas, D. J. Plata, D. P. Sawick, Tetrahedron: Asym-
metry 1997, 8, 1791–1795; e) C. Dagoneau, A. Tomassini, J.-N.
Denis, Y. Vallée, Synthesis 2001, 1, 150–154.
[3] a) For a review, see: V. Jager, P. A. Colinas, in: Synthetic Appli-
cations of 1,3-Dipolar Cycloaddition Chemistry toward Hetero-
cycles and Natural Products (Ed.: A. Padwa), John Wiley &
Sons, Hoboken, 2002, vol. 59, p 361–472; for representative
examples, see: b) M. V. Yermolina, J. Wang, M. Caffrey, L. L.
Rang, D. J. Wardrop, J. Med. Chem. 2011, 54, 765–781; c) S.
Grecian, V. V. Fokin, Angew. Chem. 2008, 120, 8409–8411; An-
gew. Chem. Int. Ed. 2008, 47, 8285–8287; d) D. Gonzalez-Cruz,
D. Tejedor, P. de Armas, F. Garcia-Tellado, Chem. Eur. J. 2007,
13, 4823–4832; e) F. Himo, T. Lovell, R. Hilgraf, V. V. Ros-
tovtsev, L. Noodleman, K. B. Sharpless, V. V. Fokin, J. Am.
Chem. Soc. 2005, 127, 210–216; f) T. V. Hansen, P. Wu, V. V.
Fokin, J. Org. Chem. 2005, 70, 7761–7764.
[10]
For representative references, see: a) S. Murarka, A. Studer,
Adv. Synth. Catal. 2011, 353, 2708–2714; b) D.-M. Ji, M.-H.
Xu, Tetrahedron Lett. 2009, 50, 2952–2955; c) M. Serizawa, S.
Fujinami, Y. Ukaji, K. Inomata, Tetrahedron: Asymmetry
2008, 19, 921–931; d) M. Bonanni, M. Marradi, S. Cicchi, A.
Goti, Synlett 2008, 197–202; e) A. Konishi, W. Wei, M. Kobay-
ashi, S. Fujinami, Y. Ukaji, K. Inomata, Chem. Lett. 2007, 36,
44–45; f) F. Cantagrel, S. Pinet, Y. Gimbert, P. Y. Chavant, Eur.
J. Org. Chem. 2005, 2694–2701; g) R. Fässler, D. E. Frantz, J.
Oetiker, E. M. Carreira, Angew. Chem. 2002, 114, 3180–3182;
Angew. Chem. Int. Ed. 2002, 41, 3054–3056; h) S. Pinet, S. U.
Pandya, P. Y. Chavant, A. Ayling, Y. Vallee, Org. Lett. 2002, 4,
1463–1466.
[4] a) R. Palin, L. Abernethy, N. Ansari, K. Cameron, T.
Clarkson, M. Dempster, D. Dunn, A.-M. Easson, D. Edwards,
J. Maclean, K. Everett, H. Feilden, K.-K. Ho, S. Kultgen, P.
Littlewood, D. McArthur, D. McGregor, H. McLuskey, I. Ne-
agu, S. Neale, L.-A. Nisbet, M. Ohlmeyer, Q. Pham, P. Rat-
cliffe, Y. Rong, A. Roughton, M. Sammons, R. Swanson, H.
Tracey, G. Walker, Bioorg. Med. Chem. Lett. 2011, 21, 892–
898; b) A. Kumar, R. A. Maurya, S. Sharma, P. Ahmad, A. B.
Singh, A. K. Tamrakar, A. K. Srivastava, Bioorg. Med. Chem.
2009, 17, 5285–5292; c) . M. Lautens, A. Roy, Org. Lett. 2000,
2, 555–557.
[11]
a) Ch. R. Reddy, E. Jithender, G. Krishna, G. V. Reddy, B. Ja-
gadeesh, Org. Biomol. Chem. 2011, 9, 3940–3947; b) Ch. R.
Reddy, P. Ramesh, N. N. Rao, S. A. Ali, Eur. J. Org. Chem.
2011, 2133–2141; c) Ch. R. Reddy, J. Vijaykumar, R. Gree, Syn-
thesis 2010, 21, 3715–3723; d) Ch. R. Reddy, E. Jithender, Tet-
rahedron Lett. 2009, 50, 5633–5635; e) Ch. R. Reddy, P. P. Mad-
havi, A. S. Reddy, Tetrahedron Lett. 2007, 48, 7169–7172.
[12]
[13]
Ch. R. Reddy, L. Radhika, T. P. Kumar, S. Chandrasekhar, Eur.
J. Org. Chem. 2011, 5967–5970.
For representative references, see: a) R. Sanz, D. Miguel, A.
Martínez, M. Gohain, P. G. García, M. A. F. Rodríguez, E.
Álvarez, F. Rodríguez, Eur. J. Org. Chem. 2010, 7027–7039; b)
Y. M. Pan, F. J. Zheng, H. X. Lin, Z. P. Zhan, J. Org. Chem.
2009, 74, 3148–3151; c) R. Sanz, D. Miguel, J. M. Á. Gutiérrez,
F. Rodríguez, Synlett 2008, 975–978; d) V. Maraval, C. Du-
hayon, Y. Coppel, R. Chauvin, Eur. J. Org. Chem. 2008, 5144–
5156; e) R. Sanz, D. Miguel, A. Martínez, J. M. A. Gutiérrez,
F. Rodríguez, Org. Lett. 2007, 9, 727–730.
[5] a) S. Tang, J. He, Y. Sun, L. He, X. She, Org. Lett. 2009, 11,
3982–3985; b) A. Voskiene, V. Mickevicius, Chem. Heterocycl.
Compd. 2009, 45, 1485–1488.
[6] a) A. M. Jawalekar, E. Reubsaet, F. P. J. T. Rutjes, F. L.
van Delft, Chem. Commun. 2011, 47, 3198–3200; b) J. A.
Crossley, D. L. Browne, J. Org. Chem. 2010, 75, 5351–5354; c)
C. Praveen, A. Kalyanasundaram, P. T. Perumal, Synlett 2010,
777–781; d) S. Bhosale, S. Kurhade, U. V. Prasad, V. P. Palle,
D. Bhuniya, Tetrahedron Lett. 2009, 50, 3948–3951; e) B. Willy,
F. Rominger, T. J. J. Müller, Synthesis 2008, 293–303; f) J. P.
Waldo, R. C. Larock, Org. Lett. 2005, 7, 5203–5205.
[7] For recent representative methods, see: a) H. Kawai, Y. Sugita,
E. Tokunaga, N. Shibata, Eur. J. Org. Chem. 2012, 1295–1298;
b) J. A. Burkhard, B. H. Tchitchanov, E. M. Carreira, Angew.
Chem. Int. Ed. 2011, 50, 5379–5382; c) O. Jackowski, T. Lec-
ourt, L. Micouin, Org. Lett. 2011, 13, 5664–5667; d) M. Ueda,
A. Sato, Y. Ikeda, T. Miyoshi, T. Naito, O. Miyata, Org. Lett.
2010, 12, 2594–2597; e) M. Girardin, P. G. Alsabeh, S. Lauzon,
S. J. Dolman, S. G. Ouellet, G. Hughes, Org. Lett. 2009, 11,
1159–1162; f) K. Wang, D. Xiang, J. Liu, W. Pan, D. Dong,
Org. Lett. 2008, 10, 1691–1694; g) J. P. Waldo, R. C. Larock, J.
Org. Chem. 2007, 72, 9643–9647; h) M. P. Bourbeau, J. T.
Rider, Org. Lett. 2006, 8, 3679–3680.
[8] a) N. Wada, K. Kaneko, Y. Ukaji, K. Inomata, Chem. Lett.
2011, 40, 440–442; b) E. Gayon, O. Quinonero, S. Lemouzy, E.
Vrancken, J.-M. Campagne, Org. Lett. 2011, 13, 6418–6422; c)
O. Debleds, E. Gayon, E. Ostaszuk, E. Vrancken, J.-M. Cam-
pagne, Chem. Eur. J. 2010, 16, 12207–12213; d) E. Gayon, O.
Debleds, M. Nicouleau, F. Lamaty, A. V. D. Lee, E. Vrancken,
J.-M. Campagne, J. Org. Chem. 2010, 75, 6050–6053; e) O. De-
bleds, C. D. Zotto, E. Vrancken, J.-M. Campagne, P. Re-
tailleaub, Adv. Synth. Catal. 2009, 351, 1991–1998; f) P. Asch-
wanden, D. E. Frantz, E. M. Carreira, Org. Lett. 2000, 2, 2331–
2333; g) E. J. Stoner, B. A. Roden, S. Chemburker, Tetrahedron
Lett. 1997, 38, 4981–4984.
[14]
W. Yan, Q. Wang, Y. Chen, J. L. Petersen, X. Shi, Org. Lett.
2010, 12, 3308–3311.
[15] a) In the case of 1b selective N-detosylation was observed to
give the N-tosyl indole based isoxazole 4b, because the reaction
conditions were at room temperature. b) The deprotection of
the N-sulfonyl group of nitrogen heteroaromatics with TBAF
under reflux temperatures is known, see: A. Yasuhara, T. Saka-
moto, Tetrahedron Lett. 1998, 39, 595–596.
[16] For 1d: a) The enantioselectivity was confirmed using chiral
HPLC: (Chiral pack IC 250ϫ4.6 mm, 5 μ, 4% 2-propanol in
hexanes, flow rate: 1 mLmin–1): tR = 8.74 (35.83%), 9.22
(64.16%) min. For 1e: b) Chiral HPLC: (Chiral pack IC
250ϫ4.6 mm, 5 μ, 10% 2-propanol in hexanes, flow rate:
1 mLmin–1): tR = 9.79 (8.96%), 10.57 (91.04%) min.
[17] M. Fujimoto, M. Sakai, Chem. Pharm. Bull. 1965, 13, 248–
252.
[18] For 1b, see: a) E. E. Wilson, A. G. Oliver, R. P. Hughes, B. L.
Ashfeld, Organometallics 2011, 30, 5214–5221; for 1c, see: b) ;
H. Huang, H. Jiang, H. Cao, J. Zhao, D. Shi, Tetrahedron 2012,
68, 3135–3144; 1d, see: c) X. Du, X. He, R.-G. Peng, X. Zhang,
X.-Q. Yu, Tetrahedron: Asymmetry 2011, 22, 1142–1146; 1e,
see: d) N. P. Reddy, T. C. Reddy, P. Aparoy, C. Achari, P. R.
Sridhar, P. Reddanna, Eur. J. Med. Chem. 2012, 47, 351–359;
for 1f, see: e) R. B. Lettan II, K. A. Scheidt, Org. Lett. 2005,
7, 3227–3230.
[19] M. Ueda, Y. Ikeda, A. Sato, Y. Ito, M. Kakiuchi, H. Shono,
T. Miyoshi, T. Naito, O. Miyata, Tetrahedron 2011, 67, 4612–
4615.
[9] a) V. R. Bhonde, R. E. Looper, J. Am. Chem. Soc. 2011, 133,
20172–20174; b) S. K. Patel, K. Murat, S. Py, Y. Vallee, Org.
Lett. 2003, 5, 4081–4084; c) S. Hanessian, M. Bayrakdarian,
Received: May 11, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20628
/KAP1
Date: 27-08-12 11:59:02
Pages: 8
C. Raji Reddy et al.
FULL PAPER
Nucleophilic Substitution
A mild and efficient synthesis of prop-
argylic N-hydroxylamines from propargylic
alcohols used as alkylating agents is de-
scribed. The method was successfully ex-
tended to a one-pot synthesis of 3,5-disub-
stituted isoxazoles through a detosylative
5-endo-dig cyclization.
C. Raji Reddy,* J. Vijaykumar,
E. Jithender, G. P. K. Reddy,
R. Grée ............................................. 1–8
One-Pot Synthesis of 3,5-Disubstituted
Isoxazoles from Propargylic Alcohols
through Propargylic N-Hydroxylamines
Keywords: Synthetic methods / Nitrogen
heterocycles / Alkylation / Propargylic al-
cohol / Isoxazole
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0