Synthesis of O-glycosyl α-aryl nitrones

Article abstract of DOI:10.1016/j.cclet.2010.04.006

α-Aryl nitrone are one of the most useful kinds of nitrones and have been extensively explored in recent years. However, the sugar moieties have not been introduced into these molecules before. We presented here an efficient synthesis of α-aryl nitrone O-

Full text of DOI:10.1016/j.cclet.2010.04.006

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1075–1078
www.elsevier.com/locate/cclet
Synthesis of O-glycosyl a-aryl nitrones
*
Ying Fu , Huai Yuan Zhang, Yan Hua Liu, Xue Feng Li,
Dan Feng Huang, Yu Lai Hu
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education,
Key Laboratory of Polymer Material of Gansu Province, College of Chemistry & Chemical Engineering,
Northwest Normal University, Lanzhou 730070, China
Received 12 January 2010
Abstract
a-Aryl nitrone are one of the most useful kinds of nitrones and have been extensively explored in recent years. However, the
sugar moieties have not been introduced into these molecules before. We presented here an efficient synthesis of a-aryl nitrone O-
glycosides via condensation of N-substituted hydroxylamine and aryl aldehydes glycosides in benzene.
# 2010 Ying Fu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Nitrones; Glycosides; Aryl aldehyde; Hydroxylamine; Synthesis
Nitrones, the N-oxide of imines, are useful synthons in organic chemistry [1]. The 1,3-dipolar structure endows
nitrone with various reactivities and have been extensively explored in the synthesis of various kinds of nitrogen
containing compounds, especially bioactive alkaloids such as DMDP [2] and hyacinthacine [3]. In fact, nitrones were
first used to trap free radicals in chemical and biochemical systems, particularly the a-aryl nitrone have found
extensively usages in these areas [4]. Several nitrones such as a-phenyl-tert-butylnitrone (PBN) and CPI-1429 have
been shown to have potent biological activity and some derivatives of PBN are now undergone extensive commercial
development for stroke [5].
Sugar nitrone, in which a sugar moiety was incorporated into a nitrone molecule, have found fundamental usages in
chemistry and biochemistry [6]. The introduction of a sugar moiety into nitrone can both improve the solubility of
nitrone in water and reduce their toxicity towards living cell. Still, the sugar moiety is a most useful chiral moiety in
asymmetric chemistry, in view of their potential medicinal significance and pharmaceutical applications, the
development of the synthetic procedures and utilities of glycosyl nitrone are of very importance.
There are kinds of standard synthetic routes to a-aryl nitrones [7] and procedures for their preparation are
continuing appeared in literature in the past years such as microwave irradiation [8] and solvent free ball-mill
procedure [9]. Although, majority nitrone-forming reactions are dehydration of substituted hydroxylamine with
carbonyl compounds in anhydrous conditions, it was also found that this kind of nitrone can be prepared in aqueous
condition [10]. We are interested in O-glycosyl a-phenyl nitrones and expect to study their behavior in both
* Corresponding author.
E-mail address: fu_yingmail@126.com (Y. Fu).
1001-8417/$ – see front matter # 2010 Ying Fu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.04.006

1[(Schme_1)TD$FIG] 076
Y. Fu et al. / Chinese Chemical Letters 21 (2010) 1075–1078
Scheme 1. Reagent and condition: (a) benzene, reflux.
asymmetric chemistry and biological system. Here we would like to report for the first time a general high-yielding
procedure for the synthesis of O-glycosyl a-aryl nitrones, a new type of sugar nitrone, by condensation of O-
glycosylated benzaldehydes with hydroxylamines. To study the generality of this procedure, glucose and lactose were
selected as the model of mono and disaccharide.
Eight a-aryl nitrone glycosides 3a–h was synthesized as described in Scheme 1. 2,3,4,6-Tetra-O-acetyl-D-
glucopyranosyl bromide and 2,3,6,20,30,40,60-hepta-O-acetyl-a-lactosyl bromide was synthesized from D-glucose
and D-lactose by conventional method and condensated with benzaldehydes following the same condition as
described by Wang et al. to give the corresponding O-benzaldehyde glycosides 1 [11]. Most of the benzaldehyde
glycosides could be easily crystallized from their mother solution to give pure b-glycopyranoside in
45–65% yields. Refluxing of glycosides with N-substituted hydroxylamines 2a (N-phenyl hydroxylamine) or 2b
(N-benzyl hydroxylamine) in benzene for 3–6 h to give, after chromatography, a-aryl nitrone glycosides 3a–h in
high yields.
1. Experimental
Melting points were recorded using a digital melting-point apparatus (WRS-1B) and are uncorrected. 1H NMR
spectra were determined at 400 MHz using a MERCURY 400 plus spectrophotometer. FT-IR spectra were
recorded using an FTS 3000 MX spectrophotometer; Mass Spectra were obtained on a VG ZAB-HS mass
spectrometer.
The aryl aldehyde glycoside (2.0 mmol) and hydroxylamine (3.5 mmol) were dissolved in 25 mL of benzene and
was heated to reflux under nitrogen atmosphere. The reaction was monitored by TLC (thin layer chromatography) till
the aryl aldehyde glycoside was completely consumed (about 3–6 h). After cooled to room temperature, the reaction
mixture was concentrated at reduced pressure. The residue was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate 3:1 as eluant.
1.1. N-phenyl-C-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3a)
White solid, yield: 92%, mp 222–224 8C. IR (KBr) 2920, 1745, 1650, 1605, 1556, 1509, 1459, 1369, 1325,
1228, 1179, 1068, 909, 850, 760 and 688 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.05 (s, 3H), 2.06 (s, 3H), 2.07 (s,
3H), 2.09 (s, 3H), 3.91–3.95 (m, 1H), 4.18 (d, 1H, J = 12.0 Hz), 4.29 (dd, 1H, J = 12.0, 5.6 Hz), 5.15–5.22 (m,
2H), 5.30–5.35 (m, 2H), 7.08 (d, 2H, J = 8.0 Hz), 7.47–7.52 (m, 3H), 7.76–7.78 (m, 2H), 7.89 (s, 1H), 8.41 (d, 2H,
J = 8.4 Hz); 13C NMR (100 MHz, CDCl3): d 170.55, 170.19, 169.39, 169.27, 158.16, 148.87, 133.60, 130.91,
129.87, 129.16, 126.03, 121.65, 116.58, 98.40, 72.60, 72.20, 71.03, 68.15, 61.89, 20.71, 20.63, 20.60; MS(ESI) m/
z: 544.1 [M+H]+.
1.2. N-phenyl-C-2-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3b)
White solid, yield: 89%, mp 183–185 8C. IR (KBr) 1751, 1224, 1134, 1054, 1595, 1471, 1371, 911 cmꢀ1; 1H NMR
(400 MHz, CDCl3): d 1.88 (s, 3H), 2.02 (s, 3H), 2.06 (s, 3H), 2.06 (s, 3H), 3.87–3.93 (m, 1H), 4.16 (dd, 1H, J = 12.0,
4.0 Hz), 4.31 (dd, 1H, J = 12.4, 5.2 Hz), 5.12 (d, 1H, J = 7.8 Hz), 5.17 (dd, 1H, J = 10.0, 9.2 Hz), 5.31–5.40 (m, 2H),
7.06–7.07 (d, 1H, J = 8.0 Hz), 7.22–7.27 (m, 1H), 7.40–7.53 (m, 4H), 7.84–7.86 (m, 2H), 8.36 (s, 1H), 9.31 (dd, 1H,
J = 6.4, 1.6 Hz); 13C NMR (100 MHz, CDCl3): d 170.49, 170.20, 169.35, 169.56, 158.46, 148.77, 133.56, 130.78,
129.67, 129.26, 126.05, 121.21,117.58, 99.40, 72.45, 72.67, 71.21, 68.09, 61.80, 20.56, 20.43, 20.23; MS(ESI)m/z:
544.1 [M+H]+.

Y. Fu et al. / Chinese Chemical Letters 21 (2010) 1075–1078
1077
1.3. N-phenyl-C-3-methoxy-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3c)
White solid, yield: 89%, mp 58 8C. IR (KBr) 2931, 1752, 1650, 1594, 1508, 1460, 1419, 1373, 1226, 1168, 1125,
1067, 1035, 907, 771, 690 and 600 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.05 (s, 3H), 2.05 (s, 3H), 2.09 (s, 3H), 2.10
(s, 3H), 3.81–3.90 (m, 1H), 3.93 (s, 3H), 4.20 (dd, 1H, J = 12.4, 2.4 Hz), 4.28 (dd, 1H, J = 12.4, 5.2 Hz), 5.07–5.12 (m,
1H), 5.16–5.23 (m, 1H), 5.26–5.36 (m, 2H), 7.18 (d, 1H, J = 8.4 Hz), 7.45–7.52 (m, 4H), 7.76–7.78 (m, 2H), 7.89 (s,
1H), 8.63 (d, 1H, J = 1.6 Hz); 13C NMR (100 MHz, CDCl3): d 170.86, 170.52, 169.66, 169.62, 150.44, 149.08, 148.00,
134.32, 130.21, 129.44, 127.54, 123.43, 121.61, 119.26, 112.50, 100.21, 72.70, 72.35, 71.31, 68.51, 62.11, 56.20,
20.96, 20.89, 20.85; MS(ESI) m/z: 574.3 [M+H]+.
1.4. N-benzyl-C-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3d)
White solid, yield: 78%, mp 154 8C. IR (KBr) 2918, 1745, 1651, 1604, 1557, 1508, 1456, 1368, 1327, 1225, 1174,
1065, 909, 846, 758, 678, 523, 469 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.04 (s, 3H), 2.05 (s, 6H), 2.07 (s, 3H), 3.86–
3.92 (m, 1H), 4.16 (dd, 1H, J = 12.4, 2.4 Hz), 4.28 (dd, 1H, J = 12.4, 5.2 Hz), 5.04 (s, 2H), 5.14 (d, 1H, J = 7.2 Hz),
5.14–5.18 (m, 1H), 5.26–5.33 (m, 2H), 6.99 (d, 2H, J = 8.8 Hz), 7.35 (s, 1H), 7.39–7.44 (m, 3H), 7.45–7.49 (m, 2H),
8.21 (d, 2H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3): d 170.48, 170.11, 169.33, 169.20, 157.82, 133.30, 133.20,
130.37, 129.17, 128.94, 125.77, 116.43, 98.42, 72.60, 72.16, 71.06, 70.96, 68.19, 61.90, 20.64, 20.55, 20.54;
MS(ESI)m/z: 558.0 [M+H]+.
1.5. N-benzyl-C-2-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3e)
White solid, yield: 80%, mp 52–54 8C. IR (KBr) 2958, 1752, 1639, 1598, 1567, 1475, 1457, 1431, 1373, 1228,
1159, 1041, 907, 819, 760, 705, 600, 510 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.02 (s, 3H), 2.07 (s, 6H), 2.08 (s,
3H), 3.91 (ddd, 1H, J = 10.0, 5.2, 2.4 Hz), 4.16 (dd, 1H, J = 12.4, 2.4 Hz), 4.33 (dd, 1H, J = 12.4, 5.2 Hz), 5.06 (d,
2H, J = 3.2 Hz), 5.10 (d, 1H, J = 7.6 Hz), 5.16–5.22 (m, 1H), 5.33–5.40 (m, 2H), 6.95 (d, 1H, J = 8.4 Hz), 7.13 (t,
1H, J = 7.6 Hz), 7.32–7.42 (m, 4H), 7.56 (dd, 1H, J = 8.0, 2.0 Hz), 7.94 (s, 1H), 9.27 (dd, 2H, J = 8.4, 2.0 Hz); 13
C
NMR (100 MHz, CDCl3): d 170.46, 170.03, 169.65, 169.43, 153.82, 133.86, 131.23, 128.94, 128.74, 128.37,
123.29, 120.85, 113.11, 98.89, 72.18, 72.12, 71.88, 71.07, 68.26, 61.77, 20.73, 20.64, 20.58; MS(ESI) m/z: 558.0
[M+H]+.
1.6. N-benzyl-C-3-methoxy-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3f)
White solid, yield: 90%, mp 144–145 8C. IR (KBr) 2953, 1750, 1637, 1591, 1506, 1458, 1426, 1373, 1327, 1228,
1165, 1039, 909, 878, 704, 632, 603, 543 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.04 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H),
2.08 (s, 3H), 3.78–3.82 (m, 1H), 3.86 (s, 3H), 4.17 (dd, 1H, J = 12.4, 2.4 Hz), 4.27 (dd, 1H, J = 12.4, 4.8 Hz), 5.02 (dd,
1H, J = 5.6, 2.4 Hz), 5.05 (s, 2H), 5.15–5.19 (m, 1H), 5.28–5.31 (m, 2H), 7.11 (d, 1H, J = 8.0 Hz), 7.31 (dd, 1H,
J = 8.4, 2.0 Hz), 7.38 (s, 1H), 7.40–7.49 (m, 5H), 8.45 (d, 1H, J = 2.0 Hz); 13C NMR (100 MHz, CDCl3): d 170.59,
170.24, 169.39, 169.34, 150.09, 147.24, 133.76, 133.04, 129.21, 129.03, 128.99, 127.04, 122.41, 118.99, 111.97,
100.27, 72.41, 72.01, 71.07, 71.01, 68.22, 61.82, 55.87, 20.68, 20.58; MS(ESI) m/z: 588.3 [M+H]+.
1.7. N-benzyl-C-4-methoxy-3-(2,3,4,6-tetra-O-acetyl-D-glucopyranosyloxy)phenyl nitrone (3g)
White solid, yield: 75%, mp 132–134 8C. IR (KBr) 2949, 1748, 1635, 1600, 1510, 1434, 1373,1326, 1236,
1125, 1055, 901, 752, 703, 613, 509, 459 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 2.01 (s, 3H), 2.03 (s, 3H), 2.04 (s,
3H), 2.06 (s, 3H), 3.82–3.84 (m, 1H), 3.85 (s, 3H), 4.17 (dd, 1H, J = 12.0, 2.0 Hz), 4.29 (dd, 1H, J = 12.4, 4.8 Hz),
5.02 (s, 2H), 5.0–5.10 (m, 1H), 5.13–5.20 (m, 1H), 5.24–5.32 (m, 2H), 6.90 (d, 1H, J = 8.8 Hz), 7.30 (s, 1H),
7.38–7.43 (m, 3H), 7.45–7.48 (m, 2H), 7.88 (dd, 1H, J = 8.8, 2.0 Hz), 8.22 (d, 1H, J = 2.0 Hz); 13C NMR
(100 MHz, CDCl3): d 170.71, 170.20, 169.42, 169.34, 152.03, 145.37, 133.36, 133.25, 129.14, 128.94, 125.74,
125.70, 123.67, 119.05, 111.87, 100.18, 72.65, 72.09, 71.11, 70.90, 68.18, 61.75, 55.97, 20.67, 20.61; MS(ESI) m/
z: 588.3 [M+H]+.

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Y. Fu et al. / Chinese Chemical Letters 21 (2010) 1075–1078
1.8. N-phenyl-C-4-(2,3,4,6,20,30,60-hepta-O-acetyl-b-D-lactosyloxy)phenyl nitrone (3h)
White solid, yield: 82%, mp 118–119 8C. IR (KBr) 2969, 1751, 1634, 1601, 1555, 1505, 1456, 1429, 1372, 1227,
1174, 1067, 902, 848, 765, 690, 606 cmꢀ1; 1H NMR (400 MHz, CDCl3): d 1.98 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 2.08
(s, 3H), 2.09 (s, 3H), 2.09 (s, 3H), 2.17 (s, 3H), 3.67–3.72 (m, 2H), 3.83–3.89 (m, 2H), 4.07–4.18 (m, 3H), 4.51 (dd, 1H,
J = 11.6, 1.6 Hz), 4.53 (d, 1H, J = 8.0 Hz), 4.98 (dd, 1H, J = 10.4, 3.6 Hz), 5.15 (dd, 1H, J = 10.4, 8.0 Hz), 5.18 (d, 1H,
J = 7.6 Hz), 5.32 (t, 1H, J = 8.4 Hz), 5.36 (dd, 1H, J = 2.4, 0.8 Hz), 7.06 (d, 2H, J = 8.8 Hz), 7.45–7.52 (m, 3H), 7.76–
7.78 (m, 2H), 7.89 (s, 1H), 8.40 (d, 2H, J = 8.8 Hz); 13C NMR (100 MHz, CDCl3): d 170.37, 170.32, 170.14, 170.06,
169.73, 169.58, 169.11, 158.16, 148.80, 133.72, 130.93, 129.88, 129.15, 125.89, 121.63, 116.50, 101.14, 97.93, 76.12,
72.88, 72.68, 71.29, 70.68, 68.95, 66.56, 66.45, 61.96, 60.78, 20.74, 20.64, 20.5; MS(ESI) m/z: 832.3 [M+H]+.
2. Results and conclusion
In conclusion, we have developed a practical, high yield method for the preparation of a-aryl nitrone glycosides
from the corresponding a-aryl aldehyde glycosides. The salient features of this method include comparably high
yields and easy manipulation. All of the eight a-aryl nitrone glycosides are new compounds and have been fully
1
characterized by means of FT-IR, H NMR, 13C NMR and ESI-MS.
Acknowledgments
The authors are grateful for financial support from National Natural Science Foundation of China (No. 20962017)
and the Natural Science Foundation of Gansu Province, China (No. 2007GS03630).
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