Synthesis of isoxazole conjugates of sugars via 1,3-dipolar cycloaddition

Article abstract of DOI:10.1139/V07-145

Isoxazole conjugates of sugar have been synthesized by the aid of 1,3-dipolar cycloaddition in a click chemistry approach. The sugar-derived propargyl ethers underwent 1,3-dipolar cycloadditions smoothly with in situ generated nitrile oxides from aromatic aromatic in good yields. The reaction exhibited a high degree of regioselectivity.

Full text of DOI:10.1139/V07-145

138
Synthesis of isoxazole conjugates of sugars via
1,3-dipolar cycloaddition
Vipraja V. Vaidya, Karuna S. Wankhede, Manikrao M. Salunkhe, and
Girish K. Trivedi
Abstract: Isoxazole conjugates of sugar have been synthesized by the aid of 1,3-dipolar cycloaddition in a click chem-
istry approach. The sugar-derived propargyl ethers underwent 1,3-dipolar cycloadditions smoothly with in situ generated
nitrile oxides from aromatic oximes in good yields. The reaction exhibited a high degree of regioselectivity.
Key words: isoxazole conjugates, 1,3-dipolar cycloadditions, nitrile oxides.
Résumé : Faisant appel à une cycloaddition 1,3-dipolaire et une approche chimique qui marche très bien, on a réalisé
la synthèse d’isoxazoles conjugués à un sucre. Les éthers propargyliques dérivés du sucre donnent lieu en douceur et
avec de bons rendements à des réactions de cycloaddition 1,3-dipolaire avec les oxydes de nitrile générés in situ à par-
tir d’oximes aromatiques. La réaction présente un degré élevé de régiosélectivité.
Mots–clés : produits conjugués de l’isoxazole, cycloadditions 1,3-dipolaires, oxydes de nitrile.
[Traduit par la Rédaction] Vaidya et al. 141
Introduction
portance of the isoxazole moiety has encouraged us to report
our results.
Several compounds of natural and non-natural origin com-
prised of the isoxazole moiety possess a broad spectrum of
biological properties viz., fungicidal, antibacterial, anti-
inflammatory, anti-allergic, anti-tumor, herbicidal, etc. The
isoxazole class of compounds are also synthetically impor-
tant as 1,3-dicarbonyl equivalents (1). Among the plethora
of protocols reported for the synthesis of the isoxazole skel-
eton, two major routes are the 1,3-dipolar cycloadditon of
alkenes and alkynes with nitrile oxides and the reaction of
hydroxylamine with a three-carbon atom component, such as
1,3-diketone or an α,β-unsaturated ketone. 1,3-Dipolar
cycloaddition has proven particularly valuable for the con-
struction of complex five-membered conformationally rigid
heterocycles (2). Isoxazoles, also among the five-membered
heterocycles, can be accessed by 1,3-dipolar cycloaddition
reaction. In particular, nitrile oxides undergo cycloaddition
with alkynes resulting in good yields of isoxazoles (3). A
similar class of compounds, i.e., triazoles, have been synthe-
sized via 1,3-dipolar cycloaddition of azides and alkynes.
This reaction has been considered as the prototype of click
chemistry (4). There are several excellent contributions from
various groups in the domain of click chemistry, wherein
1,3–dipolar cycloadditions are employed as a tool to conju-
gate molecules of structural diversity (5). Such linkage may
result in altogether new attributes and (or) an ensemble of
attributes. The continuing interest in this field and the im-
Results and discussion
We herein report regioselective syntheses of sugar conju-
gates of isoxazoles (1–10) via 1,3-dipolar cycloaddition of
carbohydrate derived alkynes and in situ generated nitrile
oxides from oximes (Scheme 1). D-Glucose was utilized as a
precursor to prepare all dipolarophiles i.e., sugar alkynes.
The dipolarophiles (1a–5a) were synthesized following stan-
dard procedures. The dipoles, i.e., nitrile oxides, were gener-
ated in situ from the biphasic oxidation of the oximes with
NaOCl in dichloromethane-triethyl amine (6). These dipoles
underwent cycloaddition with dipolarophiles to afford
cycloadducts, i.e., new isoxazole conjugates of sugars in
good yields.
D-Glucose was utilized to synthesize 1,2:5,6 diisopropyli-
dene-α-D-glucofuranose, which was subsequently subjected
to etherification using propargyl bromide to yield the
dipolarophile 1a. The dipolarophile 1a upon treatment with
benzonitrile oxide, 4-methoxy benzonitrile oxide, and 3,4-
dimethoxy benzonitrile oxide afforded cycloadducts (1–3) in
75%–80% yields.
The dipolarophile 2a was also treated with the three previ-
ously mentioned nitrile oxides separately to generate corre-
sponding cycloadducts (4–6) in 69%–75% yields. The
dipolarophile 3a was treated with benzonitrile oxide to yield
cycloadduct 7 in 74% yield. The dipolarophile 4a was ac-
cessed by Ferrier O-glycosylation of 3,4,6-tri-O-acetyl-D-
glucal with propargyl alcohol. It was further subjected to
1,3-dipolar cycloaddition with benzonitrile oxide to yield
cycloadduct 8 in 67% yield.
Received 22 October 2007. Accepted 23 November 2007.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 17 January 2008.
V.V. Vaidya, K.S. Wankhede, M.M. Salunkhe,1 and
G.K. Trivedi. Department of Chemistry, The Institute of
Science, 15-Madam Cama Road, Mumbai 400 032, India.
Our next objective was to synthesize bis-isoxazole deriva-
tives, and in that direction we carried out the propargylation
of the cycloadduct 7 to have one more site for cycloaddition
1Corresponding author (e-mail: mmsalunkhe@hotmail.com).
Can. J. Chem. 86: 138–141 (2008)
doi:10.1139/V07-145
© 2008 NRC Canada

Vaidya et al.
139
Scheme 1. Synthesis of isoxazole conjugates of sugars.
δ: 169.09, 162.35, 130.04, 128.87, 128.80, 126.72, 111.96,
109.18, 105.18, 101.10, 82.66, 82.26, 81.06, 72.14, 67.47,
63.37, 26.84, 26.72, 26.15, 25.33.
Ar
N
OH
O
Sugar
N
O
O
Sugar
CH2Cl2, NaOCl, Et3N
0 °C–RT, 8–10 h
Cycloadduct 2
Ar
27
[α]D –19.84 (c 2.5, CHCl3). IR (cm–1): 3037, 1520,
1379, 1227, 1082. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.74
(d, 2H, J = 8.7 Hz), 6.97 (d, 2H, J = 8.7 Hz), 6.63 (s, 1H),
5.90 (d, 1H, J = 3.6 Hz), 4.80 (s, 2H), 4.59 (d, 1H, J =
3.6 Hz), 4.35 (dd, 1H, J = 5.8, 13.3 Hz), 4.16–4.10 (m, 3H),
4.02 (dd, 1H, J = 5.2, 8.5 Hz), 3.85 (s, 3H), 1.49 (s, 3H),
1.43 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 168.87, 162.02, 161.07, 128.22, 121.38,
114.33, 112.03, 110.81, 109.24, 105.26, 100.94, 82.77,
82.34, 81.15, 72.24, 67.54, 63.46, 55.36, 26.91, 26.82,
26.22, 25.41.
Ar = Phenyl
Sugar =
D
-glucose
= 4-methoxyphenyl
= 3,4-dimethoxyphenyl
to yield the dipolarophile 5a. The compound 5a was sub-
jected to cycloaddition with benzonitrile oxide and 4-
methoxy benzonitrile oxide to afford bisisoxazole 9 and
mixed bis-isoxazole 10, in 65% and 67% yields, respec-
tively. All gummy products (Table 1) were purified by silica
gel column chromatography. The reaction exhibited a high
degree of regioselectivity, which was confirmed from 1H
NMR spectra of the products. The signals in the range of
δ 6.5–6.7, as singlet for vinylic proton, indicated only 5-
substituted products were formed. Furthermore, all these
isoxazole conjugates possess a protected furanoside ring that
is accessible for elaboration after deprotection. The isoxazole
moiety present can be cleaved to yield 1,3-functionalized
compounds that can serve as handles for further manipulation.
In conclusion, we successfully employed a 1,3-dipolar
cycloaddition strategy to conjugate sugar molecules with
isoxazoles, which resulted in compounds bearing an append-
age of aromatic moieties on sugar molecules. Thus, the bio-
logical profile of isoxazole coupled with sugar through C-O
linkage was diversified. In the near future, we will continue
our efforts to synthesize novel hybrid entities using the 1,3-
dipolar cycloaddition reaction of nitrile oxides as a key step.
Cycloadduct 3
27
[α]D –15.05 (c 2.0, CHCl3). IR (cm–1): 3121, 1528,
1
1376, 1082, 853. H NMR (300 MHz, CDCl3, ppm) δ: 7.42
(d, 1H, J = 1.8 Hz), 7.28 (dd, 1H, J = 1.8, 8.1 Hz), 6.93 (d,
1H, J = 8.1 Hz), 6.63 (s, 1H), 5.91 (d, 1H, J = 3.9 Hz), 4.80
(s, 2H), 4.59 (d, 1H, J = 3.6 Hz), 4.35 (dd, 1H, J = 6.4,
13.3 Hz), 4.16–4.10 (m, 3H), 4.04–3.93 (overlapping peaks,
7H). 13C NMR (75 MHz, CDCl3, ppm) δ: 168.99, 162.17,
150.78, 149.44, 121.67, 119.99, 112.06, 111.13, 109.41,
105.30, 101.00, 82.82, 82.46, 81.20, 72.30, 67.58, 63.53,
56.08, 55.99, 26.92, 28.82, 26.26, 25.45. HRMS calcd. for
C24H32NO9 (M+H): 478.2077; found 478.2081.
Cycloadduct 4
27
[α]D –30.8 (c 2.0, CHCl3). IR (cm–1): 3038, 2946, 1384,
1228, 1081, 1024. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.77
(d, 2H, J = 3.9 Hz), 7.44 (m, 3H), 7.30 (m, 5H), 6.56 (s,1H),
5.95 (d, 1H, J = 3.6 Hz), 4.76–4.61 (m, 4H), 4.49 (d, 1H, J =
12 Hz), 4.43–4.38 (m, 1H), 3.97 (d, 1H, J = 2.7 Hz), 3.83 (d,
2H, J = 6.0 Hz), 1.48 (s, 3H), 1.31 (s, 3H). 13C NMR
(75 MHz, CDCl3, ppm) δ: 169.58, 162.36, 137.31, 130.00,
128.90, 128.51, 127.99, 127.66, 126.81, 111.78, 105.17,
101.17, 82.16, 81.69, 79.12, 71.94, 68.79, 64.28, 26.80,
26.28.
Experimental
General procedure for the preparation of isoxazole
conjugates
A solution of the aldoxime (dipole precursor) (1 mmol),
sugar alkyne (dipolarophile) (1 mmol), and triethylamine
(2 to 3 drops) in dichloromethane (10 mL) was cooled to
0 °C. To this solution, sodium hypochlorite (4%, 10 mL)
was added dropwise with stirring at 0 °C. The reaction mix-
ture was warmed to RT and stirred for 8–10 h. On the disap-
pearance of the starting material (TLC), the reaction phases
were separated and the aqueous phase was extracted with di-
chloromethane. The combined layers were washed with
brine, dried with sodium sulphate, and the solvent evapo-
rated under reduced pressure to yield the crude cycloadduct.
The crude product was chromatographed on a silica gel col-
umn. The purified products were characterized.
Cycloadduct 5
27
[α]D –28.89 (c 2.0, CHCl3). IR (cm–1): 3038, 2956,
1384, 1261, 1086. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.72
(d, 2H, J = 8.7 Hz), 7.36–7.21 (m, 5H), 6.96 (d, 2H, J =
8.7 Hz), 6.50 (s, 1H), 5.95 (d, 1H, J = 3.9 Hz), 4.73–4.59
(m, 4H), 4.49 (d, J = 12 Hz, 1H), 4.43–4.38 (m, 1H), 3.97
(d, 1H, J = 3.3 Hz), 3.83 (overlapping peaks, 5H), 1.48 (s,
3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ:
169.30, 161.96, 160.99, 137.33, 129.46, 128.51, 128.21,
128.10, 127.98, 127.69, 127.66, 121.44, 114.28, 111.78,
105.13, 100.94, 82.19, 81.71, 79.13, 71.96, 68.75, 64.25,
55.33, 26.80, 26.29.
Characterization data
Cycloadduct 1
27
[α]D –34.62 (c 2.0, CHCl3). IR (cm–1): 3037, 1525,
Cycloadduct 6
27
1383, 1232, 1082. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.80
(dd, 2H, J = 2.8, 6.4 Hz), 7.47–7.45 (m, 3H), 6.69 (s, 1H),
5.91 (d, 1H, J = 3.6 Hz), 4.82 (s, 2H), 4.60 (d, 1H, J =
3.6 Hz), 4.36 (dd, 1H, J = 5.5, 12.7 Hz), 4.16–4.10 (m, 3H),
4.02 (dd, 1H, J = 5.2, 8.5 Hz), 1.49 (s, 3H), 1.43 (s, 3H),
1.37 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
[α]D –22.7 (c 1.0, CHCl3). IR (cm–1): 3037, 2922, 1258,
1
1023. H NMR (300 MHz, CDCl3, ppm) δ: 7.41 (d, 1H, J =
1.8 Hz), 7.31 (overlapping peaks, 6H), 6.93 (d, 1H, J =
8.4 Hz), 6.53 (s, 1H), 5.95 (d, 1H, J = 3.6 Hz), 4.75–4.61
(m, 4H), 4.49 (d, 1H, J = 12 Hz), 4.43–4.38 (m, 1H), 3.97–
3.93 (overlapping peaks, 7H), 3.83 (d, 2H, J = 6 Hz), 1.49
© 2008 NRC Canada

140
Can. J. Chem. Vol. 86, 2008
Table 1. Synthesis of isoxazole conjugates of sugars.
Entry
Dipolarophile
Dipole precursor
Cycloadduct
O
O
O
O
O
O
O
O
O
O
O
O
OH
N
1.
O
O
O
O
O
O
1a
1
O
N
O
O
O
O
O
O
O
O
O
OH
N
2.
3.
O
O
MeO
1a
O
N
2
MeO
O
O
O
O
O
O
MeO
MeO
OH
N
O
O
1a
MeO
MeO
O
3
N
O
O
O
O
OH
4.
5.
6.
N
O
O
O
O
N
O
BnO
BnO
O
4
2a
OH
O
N
N
O
O
O
O
MeO
O
O
MeO
N
N
O
O
BnO
BnO
O
O
2a
5
MeO
MeO
OH
O
O
O
O
O
MeO
MeO
O
BnO
BnO
2a
6
O
O
O
HO
O
OH
7.
N
O
HO
O
N
O
O
7
3a
Ph
N
O
Ph
O
O
O
AcO
AcO
OH
OH
8.
9.
O
O
N
N
8
AcO
AcO
4a
O
O
O
O
N
O
O
N
O
O
O
O
5a
O
O
9
N
N
O
O
O
O
N
O
O
MeO
O
N
O
O
O
O
O
OH
10.
N
MeO
5a
O
10
© 2008 NRC Canada

Vaidya et al.
141
(s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ:
169.45, 162.06, 150.33, 149.22, 137.27, 128.49, 127.96,
127.64, 121.60, 119.91, 110.96, 109.21, 105.13, 100.97,
82.11, 81.65, 79.10, 71.91, 68.75, 64.29, 55.97, 55.91,
26.76, 26.25. HRMS calcd. for C27H32NO8 (M+H):
498.2128; found 498.2140.
δ: 7.75–7.68 (m, 4H); 7.42 (s, 3H), 6.92 (d, 2H, J = 8.7 Hz),
6.57 (s, 1H), 6.53 (s, 1H), 5.95 (d, 1H, J = 3.3 Hz), 4.79–
4.61 (m, 5H), 4.46–4.41 (m, 1H), 4.06 (d, 1H, J = 3.3 Hz),
3.83 (overlapping peaks, 5H), 1.49 (s, 3H), 1.32 (s, 3H). 13C
NMR (75 MHz, CDCl3, ppm) δ: 168.99, 168.60, 162.41,
161.97, 160.98, 130.11, 128.93, 128.65, 128.19, 126.78,
121.33, 114.28, 113.63, 112.00, 105.06, 101.53, 101.20,
82.46, 82.21, 78.63, 67.94, 64.20, 62.90, 55.32, 26.75,
26.27.
Cycloadduct 7
27
[α]D –39.1 (c 2.0, CHCl3). IR (cm–1): 3431, 2929, 1612,
1
1373, 1214, 1078, 1019, 853. H NMR (300 MHz, CDCl3,
ppm) δ: 7.80 (d, 2H, J = 6.6 Hz), 7.6–7.36 (m, 3H), 6.61 (s,
1H), 5.97 (d, 1H, J = 3.6 Hz), 4.83–4.65 (m, 3H), 4.40–4.21
(m, 1H), 4.10 (d, 1H, J = 2.7 Hz), 3.98–3.85 (m, 2H), 2.26
(bs, 1H), 1.50 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 168.54, 162.42, 130.13, 128.90, 128.52,
126.74, 111.91, 104.90, 101.42, 83.15, 82.32, 80.11, 62.79,
60.21, 26.66, 26.20.
Acknowledgments
We wish to thank University Grants Commission (UGC),
New Delhi, for the award of a fellowship and financial sup-
port [F-12–25/(2003)] and the Director, The Institute of Sci-
ence, Mumbai.
Cycloadduct 8
27
[α]D +44.9 (c 2.0, CHCl3). IR (cm–1): 3038, 2951, 1754,
References
1369, 1232, 1043. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.80
(d, 2H, J = 3.6 Hz), 7.46–7.44 (m, 3H), 6.60 (s, 1H), 6.04–
5.88 (m, 2H), 5.35 (d, 1H, J = 9 Hz), 5.19 (s, 1H), 4.96–4.75
(m, 2H), 4.29–4.13 (m, 3H), 2.094 (s, 3H), 2.09 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ: 170.74, 170.23, 169.12, 162.46,
130.11, 130.05, 129.51, 129.09, 128.96, 128.84, 128.39,
126.93, 126.82, 126.28, 101.39, 94.11, 67.39, 65.14, 63.93,
62.75, 60.65, 20.94, 20.77. HRMS calcd. for C20H21NO7 Na
(M+Na): 410.1216; found 410.1213.
1. P.G. Baraldi, A. Barco, S. Benetti, G.P. Pollini, and D. Simoni.
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Cycloadduct 9
27
[α]D –27.10 (c 2.0, CHCl3). IR (cm–1): 3042, 2954,
1
1609, 1234, 1099, 1028. H NMR (300 MHz, CDCl3, ppm)
δ: 7.8–7.76 (m, 4H), 7.51–7.37 (m, 6H), 6.59 (s, 1H), 6.58
(s, 1H), 5.95 (d, 1H, J = 3.6 Hz), 4.79–4.62 (m, 5H), 4.46–
4.41 (m, 1H), 4.06 (d, 1H, J = 2.7 Hz), 3.90–3.79 (m, 2H),
1.49 (s, 3H), 1.32 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
δ: 169.29, 168.57, 162.41, 130.13, 130.01, 129.09, 128.93,
128.89, 128.62, 128.38, 126.78, 126.25, 112.00, 105.07,
101.57, 101.41, 82.45, 82.71, 78.64, 68.03, 64.20, 62.85,
26.75, 26.26. HRMS calcd. for C28H29N2O7 Na (M+H):
505.1975; found 505.1988.
Cycloadduct 10
6. G. Lee. Synthesis, 508 (1982).
27
[α]D –20.74 (c 1.0, CHCl3). IR (cm–1): 3042, 2956,
1
1609, 1251, 1074, 1023. H NMR (300 MHz, CDCl3, ppm)
© 2008 NRC Canada