Synthesis and α-glucosidase inhibitory, DPPH scavenging activity of substituted 2-oxo-2H-chromen-7-yl-dihydrogen phosphate derivatives

Article abstract of DOI:10.1002/jhet.675

Series of phosphorylated coumarin derivatives (4a-j) were synthesized by Pechmann condensation, phosphorylation, and debenzylation reactions in very good yields. Thus, synthesized compounds (4a-j) were evaluated for their α-glucosidase and 1,1-diphenyl-2-picrylhydrazyl scavenging activities; few compounds showed moderate to good activity. J. Heterocyclic Chem., 00, 00 (2011). Copyright

Full text of DOI:10.1002/jhet.675

November 2011
Synthesis and a-Glucosidase Inhibitory, DPPH Scavenging
Activity of Substituted 2-Oxo-2H-chromen-7-yl-dihydrogen
Phosphate Derivatives
1251
J. Ashok Kumar,a Ashok K. Tiwari,b* A. Zehra Ali,b R. Ranga Rao,a
and B. China Rajua*
aOrganic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad-500 607, India
bPharmacology Division, Indian Institute of Chemical Technology, Hyderabad-500 607, India
*E-mail: chinarajuiict@yahoo.co.in or tiwari@iict.res.in
Received April 16, 2010
DOI 10.1002/jhet.675
Published online 20 July 2011 in Wiley Online Library (wileyonlinelibrary.com).
Series of phosphorylated coumarin derivatives (4a–j) were synthesized by Pechmann condensation,
phosphorylation, and debenzylation reactions in very good yields. Thus, synthesized compounds (4a–j)
were evaluated for their a-glucosidase and 1,1-diphenyl-2-picrylhydrazyl scavenging activities; few
compounds showed moderate to good activity.
J. Heterocyclic Chem., 48, 1251 (2011).
INTRODUCTION
We have observed a-glucosidase inhibitory and free
radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging
activity with 3,4- and 3,6-disubstituted 2H-chromenone
derivatives [5b]. In this communication, we report syn-
thesis of substituted dibenzyl-2-oxo-2H-chromen-7-yl-
phosphates and substituted 2-oxo-2H-chromen-7-yl-dihy-
drogen phosphate derivatives. The a-glucosidase inhibi-
tory, DPPH scavenging potentials and the structure activ-
ity relationship of such moieties were also discussed.
Among heterocyclic compounds, coumarin (2H-1-ben-
zopyran-2-ones) and its derivatives are important com-
pounds present in many biological systems [1]. Among
various applications of these coumarins, the pharmaceu-
tical applications are more important. Extensive studies
have been done on synthesis of coumarin compounds
owing to their wide range of biological activities [2].
Postprandial hyperglycemia (PPHG) remains a serious
public health problem of diabetes and cardiovascular disease
[3]. PPHG is an exaggerated rise in blood sugar due to ex-
cessive intake of carbohydrate rich diet. It also induces overt
free radical generation that leads to oxidative damage of
biomolecules, which is better defined as postprandial oxida-
tive stress (PPOS). PPOS is associated with higher risk for
atherosclerosis, diabetic complications, and obesity [4].
Therefore, combination of agents that reduce PPHG and
PPOS may become therapeutics of interest in combating
these multiple disorders. This could be achieved either by
dietary manipulations or by intestinal a-glucosidase inhibi-
tors that reduce the digestion and absorption of glucose
from dietary sources. a-Glucosidase inhibitory drugs such
as acarbose, voglibose, and miglitol have shown promise
in reducing PPHG, hyperinsulinemea, and burden of
PPOS.
RESULTS AND DISCUSSION
Chemistry. Phosphorylation reaction is an important
reaction in the area of pharmaceutical, natural product,
pesticide, and synthetic organic chemistry to form oxy-
gen-phosphorous bonds that generate better biologically
active molecules. ‘‘For that purpose, we applied Pech-
mann condensation of resorcinol with ethylacetoacetate
in presence of p-TsOH using toluene under reflux condi-
tions to afford 7-hydroxy-8-methylcoumarin (2b).’’ The
compound 2b on phosphorylation using dibenzyl phos-
phite in presence of N,N-diisopropylethylamine (DIPEA)
with catalytic amount of N,N-dimethylaminopyridine
(DMAP) in acetonitrile and dry CCl4 solvents at ꢀ10ꢁC
resulted 3b in 80% yield. The compound 3b was charac-
1
terized by spectral data H NMR, 13C NMR, IR, Mass,
C
V
2011 HeteroCorporation

1252
J. Ashok Kumar, Ashok K. Tiwari, A. Zehra Ali, R. Ranga Rao, and B. China Raju
Vol 48
Figure 1. 31P NMR of compound 3b.
and further confirmed by 31P NMR, where the phosphorous
appeared at d ꢀ5.08 ppm (Fig. 1). Thus, obtained compound
3b was subjected for debenzylation using 10% Pd-C in
methanol solvent resulted 4b in 98% yield (Scheme 1).
The high yield of compounds encouraged us to synthe-
size various substituted coumarins 2a–i followed by phos-
phorylation reaction that resulted phosphorylated coumarins
3a–i and subsequent hydrogenation afforded 4a–i in very
good yields. Compound 3,4-dihydro-2-oxo-2H-chromen-7-
yl-dihydrogen phosphate (4j) was obtained when 3a was
1
Compound 4b was characterized by H NMR, 13C NMR,
IR, Mass, and 31P (d ꢀ0.02 ppm, Fig. 2) spectral data.
Scheme 1. Synthesis of 2-oxo-2H-chromen-7-yl-dihydrogen phosphate derivatives.
Journal of Heterocyclic Chemistry
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November 2011 Synthesis and a-Glucosidase Inhibitory, DPPH Scavenging Activity of Substituted
2-Oxo-2H-chromen-7-yl-dihydrogen Phosphate Derivatives
1253
Figure 2. 31P NMR of compound 4b.
subjected to hydrogenation for 2 h, and the double bond of
coumarin 4a [6] was found reduced. Among the synthesized
compounds 3a–i and 4a–j, compounds 3a, 4a [6], and 4c [7]
are known compounds. Compounds 3a–i and 4a–j were
screened in vitro for a-glucosidase inhibitory and DPPH free
radical scavenging activities (Tables 1 and 2).
We could not get the appreciable level of a-glucosi-
dase inhibition with benzylated phosphonocoumarins.
Therefore, we made an effort to debenzylate these cou-
marins (3a–i) under hydrogenation conditions to make
hydroxyphosphorylated coumarins (4a–j, Table 2). To
our surprise, the DPPH scavenging activity increased
more than 1.5 times, and all the chromenyldihydrogen
phosphates displayed better a-glucosidase inhibition
than benzylated phosphorylated coumarins. In this case,
we also observe that 4-methyl-2-oxo-2H-chromen-7-yl-
dihydrogen phosphate (4c, IC50; 61.76) displayed better
a-glucosidase inhibition than methyl at eighth position
(4b). Substitution of methyl at fourth and eighth position
(4d, IC50; 94.70) could not influence a-glucosidase
activity. However, the compound (4e) having phenyl
substitution at fourth position and methyl substitution at
eighth position appreciably enhanced a-glucosidase
inhibitory potential (IC50; 80.05). Absence of eighth
methyl (4g, 4h) drastically reduced a-glucosidase in-
hibition when compared with (4i). In contrast to lower
a-glucosidase inhibition activity of the bis(dibenzyl
ester) 3f, debenzylated bis(dihydrogenphosphate) 4f shows
Biology. DPPH free radical scavenging and rat intes-
tinal a-glucosidase inhibitory activity potentials are pre-
sented in Tables 1 and 2. Table 1 describes the substi-
tuted dibenzyl-2-oxo-2H-chromen-7-yl-phosphate activ-
ities of 3a–i. It was observed that all the compounds
displayed similar DPPH free radical scavenging poten-
tial at primary concentration of 25 lg/mL. 4-Methyl
(3c) and 3-chloro-4-methyl (3h) substitutions improve
the a-glucosidase inhibition activity of 3a, rather than 8
methyl (3b), 4,8-dimethyl (3d), 3-chloro-4,8-dimethyl
(3i), and 4-phenyl-8-methyl (3e) derivatives. On the
other hand, further phosphorylation on eighth position
(3f) or 4-chloromethyl (3g) could not improve a-gluco-
sidase inhibitory potential. Substitution of chloro at third
position (3h) significantly improved a-glucosidase inhi-
bition activity.
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Vol 48
Table 1
EXPERIMENTAL
Synthesis of dibenzyl 2-oxo-2H-chromen-7yl phosphate derivatives
and their activity profiles.
1H NMR, 13C NMR, and 31P NMR spectra were recorded
on a Varian, Gemini 200, and Avance 300 MHz spectrometer
in CDCl3 and CH3OH-d4 with TMS as internal standard. IR
spectra were recorded on Nicollet 740 FT spectrometer. EI-MS
obtained on 7070H spectrometer operating at 70 eV using a
% AGH
inhibition
(IC50, lM)
% DPPH
Scavenging
Entry
a
Compound (3)
26.23
24.50
20.32
0.00
0.00
Table 2
Synthesis of 2-oxo-2H-chromen-7yl-dihydrogen phosphate derivatives
and their activity profiles.
b
c
% AGH
inhibition
11.65
% DPPH
Scavenging
Entry
Compound (4)
(IC50, lM)
a
45.32
36.82
41.00
65.54
27.43
d
e
21.41
26.20
0.00
0.00
b
c
61.76 (97.41)
d
e
27.46
42.24
69.15 (94.70)
70.73 (80.05)
f
56.59
12.03
g
h
i
31.52
21.50
25.84
9.02
55.59
0.00
f
63.86
66.13 (523.48)
g
h
i
31.02
37.63
44.43
46.32
21.27
18.99
% DPPH scavenging activity is based on values obtained with primary
screening concentration of 25 lg/mL and that for a-glucosidase inhibi-
tion concentration was 100 lg/mL. Values in parentheses represent
lM IC50 value for the respective compound. AGH; a-glucosidase.
66.65 (523.49)
improved enzyme inhibition activity. On the other hand,
it is important to note that reduction of chromenone to
chromanone (4j; 3,4-dihydro derivative of 4a) displayed
lower a-glucosidase inhibition potential.
j
15.09
In conclusion, phosphorylated coumarin derivatives
3a–i were synthesized by the Pechmann condensation
and phosphorylation reaction, subsequent debenzylation
resulted in 4a–j. Compound 4e, which has phenyl at fourth
position and methyl at eighth position, displayed better
a-glucosidase inhibition with DPPH scavenging activity.
% DPPH scavenging activity is based on values obtained with primary
screening concentration of 25 lg/mL and that for a-glucosidase inhibi-
tion concentration was 100 lg/mL. Values in parentheses represent
lM IC50 value for the respective compound. AGH; a-glucosidase.
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November 2011 Synthesis and a-Glucosidase Inhibitory, DPPH Scavenging Activity of Substituted
2-Oxo-2H-chromen-7-yl-dihydrogen Phosphate Derivatives
1255
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
.
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Vol 48
(MeOH-d4): d 7.76–7.82 (m, 1H, aromatic), 7.18–7.40 (m, 2H,
aromatic), 6.28 (d, 1H, aromatic), 2.30 (s, 3H, CH3). 13C
NMR (MeOH-d4): d 162.93, 154.36, 154.18, 145.80, 127.17,
119.13, 117.94, 116.88, 115.14, 8.90. 31P NMR (MeOH-d4):
d ꢀ0.023. Mass (LC-MS): m/z 255 [MꢀH]. HRMS (ESI): m/z
calcd for C10H9O6P [MþH]þ 256.0136, found 256.0141.
w/v) was sonicated properly, and the supernatant was used as
a source of crude intestinal a-glucosidase after centrifugation.
In brief, 10 lL of test samples (5 mg/mL DMSO solution)
were reconstituted in 100 lL of 100 mM-phosphate buffer
(pH 6.8) in 96-well microplate and incubated with 50 lL of crude
intestinal a-glucosidase for 5 min before 50-lL substrate (5 mM,
p-nitrophenyl-a-D-glucopyranoside prepared in same buffer) was
added. Release of p-nitrophenol was measured at 405-nm spectro-
photometrically (SpectraMax plus 384, Molecular Devices, Sun-
nyvale, CA) 5 min after incubation with substrate. Individual
blanks for test samples were prepared to correct background ab-
sorbance where substrate was replaced with 50 lL of buffer. Con-
trol sample contained 10-lL DMSO in place of test samples. Per-
centage of enzyme inhibition was calculated as (1 ꢀ B/A) ꢂ 100
where [A] represents absorbance of control without test samples,
and [B] represents absorbance in presence of test samples.
4,8-Dimethyl-2-oxo-2H-chromen-7-yl-dihydrogen phos-
phate (4d). White solid; mp 122–124ꢁC. Yield: 98%. IR
(KBr): 3422, 2928, 1686, 1602, 1384, 1276, 1036, 872 cmꢀ1
.
1H NMR (MeOH-d4): d 7.58 (s, 1H, aromatic), 7.30 (s, 1H, ar-
omatic), 6.36 (s, 1H, aromatic), 2.48 (s, 3H, CH3), 2.38 (s, 3H,
CH3). 13C NMR (CDCl3): d 163.13, 155.61, 154.18, 153.74,
124.71, 123.90, 119.08, 117.67, 113.63, 18.85, 9.18. 31P NMR
(MeOH-d4): d ꢀ0.023. Mass (LC-MS): m/z 269 [MꢀH].
HRMS (ESI): m/z calcd for C11H11O6P [MþH]þ 270.02932,
found 270.03.
DPPH free radical scavenging activity. Assay for the
scavenging of stable free radical DPPH was done as reported
earlier [5]. Briefly, in a 96-well microplate, 25 lL of test
sample dissolved in DMSO (1 mg/mL), 100 lL of 0.1M tris-
HCl buffer (pH 7.4), and 125 lL of 0.5 mM DPPH solution
dissolved in absolute ethyl alcohol were added. The reaction
mixture was shaken well and incubated in dark for 30 min
and read at 517 nm spectrophotometrically (SpectraMax plus
384, Molecular Devices, Sunnyvale, CA). Percentage of
DPPH scavenging was calculated as (1 ꢀ B/A) ꢂ 100 where
A represents absorbance of control without test samples, and
B represents absorbance in presence of test samples.
8-Methyl-2-oxo-4-phenyl-2H-chromene-7-yl-dihydrogen phos-
phate (4e). Semisolid, Yield: 98%. 1H NMR (MeOH-d4): d
7.64 (d, 1H, aromatic), 6.22–6.40 (m, 6H, aromatic), 6.02
(s, 1H, aromatic), 2.52 (s, 3H, CH3). Mass (LC-MS): m/z 333
[MþH]. Anal. Cacld. for C16H13O6P: C, 57.84; H, 3.94.
Found: C, 57.79; H, 4.04.
4-Methyl-2-oxo-2H-chromen-7,8-diyl-bis(dihydrogen phos-
phate) (4f). Semisolid, Yield: 98%. IR (KBr): 3449, 2924,
1
1728, 1604, 1379, 1267, 1217, 1019, 912, 760 cmꢀ1. H NMR
(MeOH-d4): d 7.18–7.41 (m, 1H, aromatic), 6.50–6.34 (m, 1H,
aromatic), 6.10 (s, 1H, aromatic), 2.24 (s, 3H, CH3). Mass
(LC-MS): m/z 351 [MꢀH]. Anal. Cacld. for C10H10O10P2: C,
34.28; H, 2.85. Found: C, 34.19; H, 2.89.
Acknowledgments. The authors are thankful to the Head,
Organic Chemistry Division-I and Director-IICT for their con-
stant encouragement. JA is thankful to UGC, New Delhi for the
award of fellowship.
4-(Chloromethyl)-2-oxo-2H-chromene-7-yl-dihydrogen phos-
phate (4g). Solid; mp 197–199ꢁC. Yield: 98%. IR (KBr):
3426, 2925, 2855, 2309, 1679, 1614, 1393, 1247, 1168, 1043,
1
967 cmꢀ1. H NMR (MeOH-d4): d 7.60 (d, 1H, J ¼ 6.61 Hz,
aromatic), 7.17–7.29 (m, 2H, aromatic), 6.26 (s, 1H, aromatic).
Mass (LC-MS): m/z 289 [MꢀH]. Anal. Cacld. for
C10H8ClO6P: C, 41.37; H, 2.75. Found: C, 41.39; H, 2.69.
REFERENCES AND NOTES
[1] (a) O’Kennedy, R.; Thomas, R. D. Coumarins: Biology,
Applications, and Mode of Action; Wiley: Chichester, UK, 1997;
(b) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Coumarins;
Wiley: New York, 1982.
3-Chloro-4-methyl-2-oxo-2H-chromen-7-yl-dihydrogen phos-
phate (4h). Semisolid, Yield: 98%. IR (KBr): 3436, 2924,
2854, 1706, 1614, 1389, 1268, 1069, 758 cmꢀ1 1H NMR
.
(MeOH-d4): d 7.74 (s, 1H, aromatic), 7.12-7.24 (m, 1H, aro-
matic), 6.26 (s, 1H, aromatic), 2.50 (s, 3H, CH3). Mass (LC-
MS): m/z 289 [MꢀH]. Anal. Cacld. for C10H8ClO6P: C, 41.37;
H, 2.75. Found: C, 41.29; H, 2.81.
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3-Chloro-4,8-dimethyl-2-oxo-2H-chromen-7-yl-dihydrogen
1
phosphate (4i). Semisolid, Yield: 98%. H NMR (MeOH-d4):
d 7.26 (s, 1H, aromatic), 6.38 (s, 1H, aromatic), 2.48 (s, 3H,
CH3), 2.38 (s, 3H, CH3). Mass (LC-MS): m/z 327 [MþNa].
Anal. Cacld. for C11H10ClO6P: C, 43.42; H, 3.28. Found: C,
43.46; H, 3.35.
3,4-Dihydro-2-oxo-2H-chromen-7-yl-dihydrogen phosphate
(4j). Semisolid, Yield: 92%. IR (KBr): 3447, 2925, 2855,
1633, 1459, 1216, 760 cmꢀ1 1H NMR (MeOH-d4): d 7.02 (d,
1H, aromatic), 6.54–6.72 (m, 2H, aromatic), 2.58 (t, 2H, CH2),
2.86 (t, 2H, CH2). 13C NMR (MeOH-d4): d 175.70, 157.13,
131.30, 124.39, 112.05, 108.35, 115.13, 34.95, 26.56. Mass
(LC-MS): m/z 245 [MþH]. Anal. Cacld. for C9H9O6P: C,
44.26; H, 3.68. Found: C, 44.22; H, 3.71.
Biological activity: a-Glucosidase inhibitory assay. a-Glu-
cosidase inhibitory activity was determined as reported earlier
[5]. Rat intestinal acetone powder in normal saline (100:1;
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DOI 10.1002/jhet

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2-Oxo-2H-chromen-7-yl-dihydrogen Phosphate Derivatives
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