November 2011 Synthesis and a-Glucosidase Inhibitory, DPPH Scavenging Activity of Substituted
2-Oxo-2H-chromen-7-yl-dihydrogen Phosphate Derivatives
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direct inlet system. Melting points were determined in open
glass capillary tubes on a Metler FP 51 melting point apparatus
and are uncorrected. The CHN analyses were recorded on Vario
EL analyzer. HRMS were measured on Agilent Technologies
6510, Q-TOFLC/MS ESI-Technique. All reactions were moni-
tored by thin layer chromatography (TLC) on precoated silica
gel 60 F254 (mesh); spots were visualized under UV light. Merck
silica gel (60–120; 100–200 mesh) was used for chromatography.
General procedure for the synthesis of 4-substituted
chromenones (2a–i). Resorcinol (1 mmol), ethylacetoacetate
(1.1 mmol), and p-TsOH (20 mol %) in dry toluene are
refluxed for 20 min. The crude compound on flash chromatog-
raphy using silica gel gave 4-methyl-7-hydroxy-2H-2-chrome-
none (2a) in 90% yield. Similarly, the compounds (2b and 2i)
were prepared by using the corresponding b-ketoesters.
General procedure for the synthesis of phosphorylated
chromenones (3a–i). The 7-hydroxy-8-methylcoumarin (2b, 1
mmol) and the anhydrous acetonitrile (5 mL) are charged to
an oven-dried three-necked round-bottom flask fitted with
septa containing a stir bar under nitrogen atmosphere. The
mixture was cooled to ꢀ10ꢁC, CC14 (10 equiv), DIPEA (2.1
equiv) followed by DMAP (0.1 equiv) and dibenzyl phosphite
(1.5 equiv) was added and the contents were stirred at the
same temperature for 10 h. After completion of the reaction
(TLC), 0.5M aqueous KH2PO4 (32 mL/100 mL H2O) was
added at 0ꢁC, and the mixture was extracted with ethyl acetate
(3 ꢂ 30 mL), the organic phase was washed with water and
saturated aqueous NaC1, dried over Na2SO4, and the crude
product was purified by column chromatography using silica
gel to give dibenzyl-8-methyl-2-oxo-2H-chromen-7-yl-phos-
phate (3b) in 86% yield.
Dibenzyl-8-methyl-2-oxo-4-phenyl-2H-chromen-7-yl-phos-
phate (3e). White solid; mp 86–88ꢁC. Yield: 72%. IR (KBr):
3425, 3057, 2924, 1724, 1600, 1371, 1283, 1017, 925 cmꢀ1
.
1H NMR (CDCl3): d 7.36–7.42 (m, 3H, aromatic), 7.26–7.33
(m, 2H, aromatic), 7.16–7.24 (m, 10H, aromatic), 7.04–7.15
(m, 2H, aromatic), 6.16 (s, 1H, aromatic), 5.04 (d, 4H, OCH2),
2.22 (s, 3H, CH3). 13C NMR (CDCl3): d 160.39, 155.52,
135.38, 135.19, 135.10, 129.69, 128.88, 128.76, 128.62,
128.53, 128.39, 128.07, 127.94, 124.84, 116.05, 113.92, 70.33,
70.26, 9.16. 31P NMR (CDCl3): d ꢀ5.075. Mass (LC-MS): m/z
513 [Mþ1]. HRMS (ESI): m/z calcd for C30H25O6P [MþH]þ
512.13888, found 512.13972.
Tetrabenzyl-4-methyl-2-oxo-2H-chromene-7,8-diyl-diphos-
phate (3f). Semisolid, Yield: 68%. IR (KBr): 3064, 2956,
2924, 2855, 2337, 1736, 1611, 1574, 1450, 1382, 1280, 1013,
1
917, 871, 738, 694 cmꢀ1. H NMR (CDCl3): d 7.21–7.44 (m,
22H, aromatic), 6.26 (s, 1H, aromatic), 5.34 (d, 4H, OCH2),
5.08 (d, 4H, OCH2), 2.42 (s, 3H, CH3). Mass (LC-MS): m/z
713 [MþH]. Anal. Cacld. for C38H34O10P2: C, 64.05; H, 4.81.
Found: C, 64.10; H, 4.78.
Dibenzyl-4-(chloromethyl-2-oxo-2H-chromen-7-yl-phosphate
(3g). Semisolid, Yield: 70%. IR (KBr): 3413, 2924, 1713,
1
1655, 1607, 1449, 1239, 926 cmꢀ1. H NMR (CDCl3): d 7.50
(d, 1H, aromatic), 7.21–7.32 (m, 10H, aromatic), 7.06 (dd, 1H,
aromatic), 6.96 (d, 1H, aromatic), 6.42 (s, 1H, aromatic), 5.09
(d, 4H, OCH2), 4.55 (s, 2H, CH2Cl). Mass (LC-MS): m/z 471
[MþH]. Anal. Cacld. for C24H20ClO6P: C, 61.27; H, 4.25.
Found: C, 61.18; H, 4.27.
Dibenzyl-3-chloro-4-methyl-2-oxo-2H-chromen-7-yl-phosphate
(3h). Semisolid, Yield: 70%. IR (KBr): 3421, 2924, 2855,
1
1729, 1612, 1552, 1275, 1146, 1016, 880, 730 cmꢀ1. H NMR
Dibenzyl-8-methyl-2-oxo-2H-chromen-7-yl-phosphate (3b).
Semisolid, Yield: 82%. IR (KBr): 3405, 2924, 2855, 1731,
(CDCl3): d 7.52 (d, 1H, aromatic), 7.28–7.38 (m, 10H, aro-
matic), 7.12 (dd, 1H, aromatic), 7.02 (d, 1H, aromatic), 5.14
(d, 4H, OCH2), 2.59 (s, 3H, CH3). Mass (LC-MS): m/z 471
[MþH]. Anal. Cacld. for C24H20ClO6P: C, 61.27; H, 4.25.
Found: C, 61.25; H, 4.32.
1
1605, 1492, 1556, 1380, 1246, 1017, 958, 755 cmꢀ1. H NMR
(CDCl3): d 7.66 (d, 1H, aromatic), 7.22–7.38 (m, 12H, aro-
matic), 6.36 (d, 1H, aromatic), 5.12 (d, 4H, OCH2), 2.26
(s, 3H, CH3). 13C NMR (CDCl3): d 160.59, 153.01, 143.29,
134.95, 128.73, 128.56, 128.48, 128.00, 127.70, 125.57,
116.33, 115.18, 115.02, 70.37, 70.29, 8.76. 31P NMR (CDCl3):
ꢀ5.07. Mass (LC-MS): m/z 437 [MþH]. Anal. Cacld. for
C24H21O6P: C, 66.05; H, 4.81. Found: C, 66.02; H, 4.85.
Dibenzyl-3-chloro-4,8-dimethyl-2-oxo-2H-chromen-7-yl-
phosphate (3i). Semisolid, Yield: 76%. IR (KBr): 3391,
2927, 1687, 1603, 1386, 1278, 1110, 1037, 872 cmꢀ1 1H
.
NMR (CDCl3): d 7.24–7.39 (m, 12H, aromatic), 5.15 (d, 4H,
OCH2), 2.58 (s, 3H, CH3), 2.28 (s, 3H, CH3). 13C NMR
(CDCl3): d 147.54, 128.78, 128.60, 128.49, 128.04, 127.63,
122.60, 116.65, 70.43, 70.34, 16.32, 9.02. Mass (LC-MS): m/z
485 [MþH]. Anal. Cacld. for C25H22ClO6P: C, 61.98; H, 4.54.
Found: C, 61.92; H, 4.59.
General procedure for the debenzylation of phosphoryl-
ated chromenones (4a–i). Dibenzyl-8-methyl-2-oxo-2H-chro-
men-7-yl-phosphate (3b, 1 mmol) in anhydrous methanol (5
mL) was charged to an oven-dried two-necked round-bottom
flask fitted with septa containing a stir bar under nitrogen
atmosphere. The Pd-C (10%) was charged, equipped with
hydrogen balloon, and the contents were stirred at room tem-
perature for 0.5–1 h. After completion of the reaction (TLC), the
mixture was filtered through celite and washed with methanol (3
ꢂ 30 mL), the organic layer was dried over Na2SO4, and the
crude product was purified by flash column chromatography
using silica gel (60:120) to give 8-methyl-2-oxo-2H-chromen-7-
yl-dihydrogen phosphate (4b) in 92% yield.
Dibenzyl-4-methyl-2-oxo-2H-chromen-7-yl-phosphate (3c).
White solid; mp 61–63ꢁC. Yield: 84%. IR (KBr): 3430, 3064,
.
2924, 1733, 1616, 1389, 1277, 1039, 895 cmꢀ1 1H NMR
(CDCl3): d 7.50 (d, 1H, aromatic), 7.30ꢀ7.42 (m, 10H, aro-
matic), 7.12 (dd, 1H, aromatic), 7.02 (s, 1H, aromatic), 6.22
(s, 1H, aromatic), 5.14 (d, 4H, OCH2), 2.42 (s, 3H, CH3). 13C
NMR (CDCl3): d 160.38, 154.12, 152.75, 152.66, 151.80,
134.97, 134.89, 128.76, 128.57, 128.09, 125.64, 117.11, 116.37,
116.31, 114.08, 108.68, 108.61, 70.37, 70.29, 18.62. 31P NMR
(CDCl3): ꢀ5.38. Mass (LC-MS): m/z 459 [MþH]. Anal. Cacld.
for C24H21O6P: C, 66.05; H, 4.81. Found: C, 65.97; H, 4.82.
Dibenzyl-4,8-dimethyl-2-oxo-2H-chromen-7-yl-phosphate (3d).
White solid; mp 94–96ꢁC. Yield: 78%. IR (KBr): 3427, 2925,
.
1724, 1602, 1378, 1279, 1089, 1037, 890 cmꢀ1 1H NMR
(CDCl3): d 7.26–7.39 (m, 12H, aromatic), 6.22 (s, 1H, aro-
matic), 5.14 (d, 4H, 2OCH2), 2.42 (s, 3H, CH3), 2.28 (s, 3H,
CH3). 13C NMR (CDCl3): 163.22, 155.53, 153.78, 124.74,
123.91, 119.07, 117.66, 113.67, 70.33, 70.24, 18.85, 8.90.
Mass (LC-MS): m/z 451 [MþH]. HRMS (ESI): m/z calcd for
C25H23O6P [MþH]þ 450.12322, found 450.12252.
8-Methyl-2-oxo-2H-chromen-7-yl-dihydrogen phosphate
(4b). Semisolid, Yield: 98%. IR (KBr): 3392, 2928, 1696,
1605, 1492, 1243, 1165, 1087, 971, 841 cmꢀ1 1H NMR
.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet