Synthesis and glycogen phosphorylase inhibitor activity of 2,3-dihydrobenzo[1,4]dioxin derivatives

Article abstract of DOI:10.1016/j.bmc.2007.03.084

Novel 5-benzyl and 5-benzylidene-thiazolidine-2,4-diones carrying 2,3-dihydrobenzo[1,4]dioxin pharmacophore were synthesized and their glycogen phosphorylase inhibitor activity was also studied.

Full text of DOI:10.1016/j.bmc.2007.03.084

Bioorganic & Medicinal Chemistry 15 (2007) 4048–4056
Synthesis and glycogen phosphorylase inhibitor activity
of 2,3-dihydrobenzo[1,4]dioxin derivatives
a,
b
c
c
a,d
*
´
´
´
´
´
´
Laszlo Juhasz, Tibor Docsa, Attila Brunyaszki, Pal Gergely and Sandor Antus
aDepartment of Organic Chemistry, University of Debrecen, H-4010, PO Box 20 Debrecen, Hungary
bCell Biology and Signaling Research Group of the Hungarian Academy of Sciences, Department of Medical Chemistry,
Research Center for Molecular Medicine, University of Debrecen, H-4012 Debrecen, PO Box 07, Hungary
cDepartment of Medicinal Chemistry, Medical and Health Science Center, University of Debrecen, H-4012 Debrecen,
PO Box 07, Hungary
dResearch Group for Carbohydrates of Hungarian Academy of Sciences, H-4010 Debrecen, PO Box 55, Hungary
Received 1 December 2006; revised 15 February 2007; accepted 30 March 2007
Available online 2 April 2007
Abstract—Novel 5-benzyl and 5-benzylidene-thiazolidine-2,4-diones carrying 2,3-dihydrobenzo[1,4]dioxin pharmacophore were
synthesized and their glycogen phosphorylase inhibitor activity was also studied.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
glitazones) (Fig. 1) results in insulin sensibilization and
antidiabetic action.
In the last decades the number of patients diagnosed
with diabetes dramatically increased and approximately
6–10% of the adult population suffer from this disease in
Western societies. Diabetes can be divided into two ba-
sic types depending on whether the patient secretes insu-
lin or not: Type I or insulin dependent diabetes mellitus
and Type II or non-insulin dependent diabetes mellitus
(NIDDB). Ninety percent of the diabetics belong to
NIDDB which can be controlled mainly by restriction
of caloric intake and by use of hypoglycemic agents.1
The most commonly used oral hypoglycemics are sulfo-
nylurea drugs which increase insulin secretion but they
can also induce serious hypoglycemia.2,3 Recent devel-
opments of new hypoglycemic agents are focused on
the synthesis of peroxisome proliferator-activated
(PPAR) receptor agonists4–8 and glycogen phosphory-
lase (GP) inhibitors.9–13
Among related compounds Troglitazone (2) was put on
the market in the USA and Japan in 1997. Although it
was withdrawn in the early 2000s due to its hepatotoxic-
ity, clinical development of other glitazones is still in
progress.20
Glycogen phosphorylase (GP) is a key enzyme in the
regulation of blood sugar level, and it catalyzes the
O
O
NH
O
NH
O
HO
O
S
S
O
O
2
1
O
O
O
N
N
S
NH
PPARs belong to the nuclear receptor superfamily14 and
they play important roles in regulation of proliferation
and differentiation of several cell types. Its activation
by thiazolidine-2,4-dione derivatives 1–515–19 (called
NH
S
O
O
O
3
4
O
F
NH
S
O
Keywords: 2,3-Dihydrobenzo[1,4]dioxin; Glyogen phosphorylase; Dia-
betes; Glitazones.
O
5
*
Corresponding author. Tel.: +36 52 512900/22476; fax: +36 52
453836; e-mail: juhaszl@delfin.unideb.hu
Figure 1. Structures of some glitazones.
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.03.084

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L. Juhasz et al. / Bioorg. Med. Chem. 15 (2007) 4048–4056
4049
HO
H
HO
HO
HO
HO
HO
HO
OH
N
O
O
O
H
N
H
N
OH
O
OH
O
HN
OH
OH
S
O
O
O
N
H
N
H
7
8
6
Figure 2. Structures of some glycogen phosphorylase inhibitors.
formation of glucose-1-phosphate from glycogen.12
Because of the biological importance in the glycogen
metabolism, GP has been exploited as a possible molec-
ular target for potent inhibitors that may be relevant to
the control of blood glucose concentrations in Type II
diabetes.21 Since several GP inhibitors 6–8 (Fig. 2) carry
a hydantoin or thiohydantoin moiety,22,23 we assumed
that glitazone-type molecules may also have glycogen
phosphorylase inhibitor activity.
eral 5-benzyl- and 5-benzylidene-thiazolidine-2,4-diones
carrying a 2,3-dihydrobenzo[1,4]dioxin moiety were syn-
thesized and tested for GP inhibitor activity.
2. Chemistry
The synthesis of 2-hydroxymethyl-2,3-dihydroben-
zo[1,4]- dioxins 19–21, 23, 33 is shown in Schemes 1
and 2 as well as in Table 1. Our synthetic approach—
except for 21, 23 and 33—was based on the transforma-
tion of 1-(2-hydroxyphenyl)ethanones 13 and 14 into the
corresponding 2-hydroxymethyl-2,3-dihydrobenzo[1,4]-
dioxins 19 and 20. In the first step 1-(2-allyloxyphe-
nyl)ethanones 15 and 16 were obtained by simple
alkylation of 13 and 14, respectively, with allyl bromide
in the presence of potassium carbonate in dry DMF at
80 ꢁC. Bayer–Villiger oxidation33 and epoxidation with
mCPBA in CHCl3 gave the epoxides 17 and 18 in
good yields (80% and 71%) which were then reacted
with NaOMe/MeOH to furnish the 2,3-dihydro-
benzo[1,4]dioxins 19 and 20 in moderate yields (45%
and 65%).
Numerous pharmacologically active molecules 9–12
(Fig. 3) possess a 2,3-dihydrobenzo[1,4]dioxin moi-
ety.24–27 This type of molecules has been widely applied
in the design of therapeutic agents with a-adrenergic
blocking,24 5-HT1A antagonist,25,26 and antihepatotox-
ic27 properties. Although several glitazones with dihy-
drobenzopyran or dihydrobenzofuran ring system were
synthesized earlier and tested as hypoglycemic agents,28
interestingly until now only a few 2,3-dihydrobenzo[1,4]-
dioxin analogues of troglitazone were tested.29
In continuation of our study on the synthesis of
biologically active O-heterocyclic compounds30–32 sev-
2-Hydroxymethyl-2,3-dihydrobenzo[1,4]dioxin (21)34 served
as a suitable starting material for the synthesis of 23.
Bromination of 21 with bromine in acetic acid in the
presence of AlCl3 afforded 22, whose saponification with
NaOMe/MeOH gave 23 in a moderate overall yield
(45%). The synthesis of 33 was based on the Dakin oxi-
dation of the aldehyde 30 (Scheme 2).32
O
O
O
O
O
O
NH
NH2
H
H
N
10
H
N
H
O
9
OH
O
O
O
OH
OH
OH
O
O
H
H
Aldehyde 30 was prepared from sesamol 29 by a simple
formylation using paraformaldehyde as the formylating
agent in the presence of dry magnesium chloride and
triethylamine in dry THF.35 Oxidation of 30 did not
serve the pirocatechin derivative 31 as a product under
the well-known conditions of Dakin oxidation. However
using triethylamine as the solvent oxidation of 30 at low
Ar
O
O
HO
H
OH
OR
11
12
Figure 3. Structures of some biologically active 2,3-dihydribenzo[1,4]-
dioxin derivatives.
R1
R2
R3
R1
R2
R3
O
R2
R1
O
O
R1
R2
OR3
O
i
ii
iii
OH
OH
O
13,14
15,16
17,18
19,20
iv
R2
R1
O
Br
Br
O
Br
Br
O
O
O
v
iii
iv
OAc
OH
OH
OTs
O
O
O
24-27
23
22
21
Scheme 1. Reagents and conditions: (i) allyl bromide/K2CO3/DMF, 80 ꢁC; (ii) MCPBA/CHCl3, reflux; (iii) NaOMe/MeOH, rt; (iv) TsCl/pyridine, rt;
(v) Br2; AlCl3/AcOH.

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4050
O
O
OH
OH
OH
O
O
OH
O
O
O
O
O
O
i
ii
iii
CHO
31a
30
31
29
O
O
O
O
O
O
O
O
O
O
iv
v
OH
OTs
O
COOEt
O
28
32
33
Scheme 2. Reagents and conditions: (i) (CHO)n, MgCl2/Et3N, THF, reflux; (ii) H2O2/Et3N, 5 ꢁC; (iii) ethyl dibromopropionate, K2CO3/acetone,
reflux; (iv) LiAlH4/dry ether; (v) TsCl/dry pyridine.
Table 2. List of the substituents of compounds 24–59 (Scheme 3)
Table 1. List of the substituents of compounds 13–27 (Scheme 2)
R1
R2
R3
Compound
R1
R2
R3
Compound
24, 34, 44
39, 49
Br
Br
H
H
H
13, 15, 17
14, 16, 18
19, 24
20, 25
26
Br
H
H
COCH3
COCH3
—
H
OMe
H
Br
H
25, 35, 45
40, 50
Br
Br
Br
H
H
OMe
H
Br
Br
H
—
—
26, 36, 46, 54
41, 51, 56
27, 37, 47
42, 52
O–CH2–O
O–CH2–O
Br
H
OMe
H
27
—
Br
Br
H
Br
Br
H
OMe
H
temperature (5 ꢁC) gave the desired product 31 which
was transformed into the ester derivative 32 without
purification in a moderate yield (58%). In the following
step reduction of 32 with LiAlH4 resulted in the
2-hydroxymethyl-2,3-dihydrobenzo[1,4]-dioxin 33 in
88% yield.
28, 38, 48, 55
43, 53, 57
58
H
H
OMe
—
—
H
Br
H
Br
59
dine-2,4-diones can be transformed into the correspond-
ing 5-benzyl derivatives by reduction with lithium
borohydride in pyridine and tetrahydrofuran.36 Surpris-
ingly, under these circumstances no transformation of
the benzylidene derivatives 44–53 could be detected. At
the same time, catalytic hydrogenation of 46, 48, 51,
and 53 in acetic acid at high pressure (12 atm) resulted
in the 5-benzyl-thiazolidine-2,4-diones 54–57 in good
yields (65–86%).
Treatment of the appropriate benzo[1,4]dioxins 19, 20,
23, and 33 with 4-methylbenzenesulfonyl chloride (TsCl)
in dry pyridine afforded the desired tosylates 24–28 with
good yields (75–90%).
Using these tosylates 24–28 as starting materials, glitaz-
ones having a 2,3-dihydrobenzo[1,4]dioxin moiety were
prepared in three steps (Scheme 3 and Table 2).
Reaction of the tosylates 24–28 with 4-hydroxybenzalde-
hyde or vanillin in the presence of potassium carbonate in
DMF gave 34–43 in good to excellent yields (72–99%).
Condensation of these compounds with thiazolidine-
2,4-dione was carried out under solvent-free conditions
by melting in the presence of sodium acetate. The desired
products 44–53 could be isolated during a work up proce-
dure by simple filtration in good yields (57–89%). It is
known from the literature that 5-benzylidene-thiazoli-
3. Biology
3.1. Assays
Phosphorylase activities were assayed in the direction of
the glycogen synthesis at 30 ꢁC with 10 lg/ml enzyme,
1% glycogen in the absence of AMP (muscle or liver
R2
R1
O
O
R2
R1
O
O
R2
R1
O
O
R3
R3
i
ii
O
OTs
O
O
S
NH
CHO
O
24-28
34-43
44-53
iii
i
R2
R1
O
R2
R1
O
R3
O
O
O
O
O
S
NH
58,59
O
54-57
Scheme 3. Reagents and conditions: (i) 4-hydroxybenzaldehyde or vanillin or phenol/K2CO3/DMF, 80 ꢁC; (ii) thiazolidine-2,4-dione, NaOAc,
140 ꢁC; (iii) H2/Pd(C), AcOH, 12 atm.

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L. Juhasz et al. / Bioorg. Med. Chem. 15 (2007) 4048–4056
4051
phosphorylase a), or in the presence of AMP (1 mM
AMP for muscle and 2 mM AMP for liver phosphory-
lase b), with or without the substrate in 50 mM trietha-
nolamine/HCl (pH 6.8) buffer, 100 mM KCl, 1 mM
dithiothreitol, and 1 mM EDTA. The kinetic studies
were performed as described previously37 except that
higher D-glucose-1-phosphate concentrations were used
for the assay of liver phosphorylases as suggested by
Stalmanas and Hers.38 The results are summarized in
Table 3.
4.1.1. 1-(2-Allyloxy-5-bromophenyl)ethanone (15). White
crystals; yield: 87%; mp: 54–56 ꢁC; H NMR: d (ppm):
1
2.62 (3H, s, CH3), 4.62 (2H, dt, J = 1.33 and 5.24 Hz,
OCH2); 5.32 (1H, dq, J = 1.33 and 10.44; CH2A); 5.42
(1H, dq, J = 1.33 and 17.23, CH2B); 6.06 (1H, m,
J = 5.24, 10.44 and 17.23, CH); 6.86 (1H, d, 8.86, H-
30); 7.52 (1H, dd, J = 2.65 and 8.86, H-40); 7.83 (1H, d,
J = 2.65, H-60). HRMS m/z 253.9938 (calcd for
C11H11BrO2: 253.9942).
4.1.2. 1-(2-Allyloxy-4-bromophenyl)ethanone (16). White
1
Due to the low solubility of the tested compounds the Ki
value could be determined only in the case of 45, 47, and
52 (Table 3). These data clearly indicated that 2,3-dihy-
drobenzo[1,4]dioxin derivative 47 possesses a comparable
GP inhibitor activity with that of 6 [Ki (GPb) = 5.1 lM]
and 7 [Ki (GPb) = 4.2 lM] (all three compounds were
tested in the same assay conditions).22 Moreover as we
assumed the glitazone-type molecules have glycogen
phosphorylase inhibitor activity.
crystals; yield 90%; mp: 65–67 ꢁC; H NMR: d (ppm):
2.6 (3H, s, CH3), 4.61 (2H, dt, J = 1.20 and 5.38 Hz,
OCH2); 5.34 (1H, dq, J = 1.20 and 10.4, CH2A); 5.42
(1H, dq, J = 1.20 and 17.3, CH2B); 6.06 (1H, m,
J = 5.38, 10.40 and 17.3, CH); 7.1 (1H, d, J = 1.7, H-
30); 7.15 (1H, dd, J = 1.7 and 8.59, H-50); 7.61 (1H, d,
J = 8.59, H-60). HRMS m/z 253. 9940 (calcd for
C11H11BrO2: 253.9942).
4.2. General procedure for the preparation of 17 and 18
4. Experimental
A solution of the allyl-ethers (15–16) (17 mmol) and
MCPBA (77%, 2.5 equiv) in chloroform was boiled under
reflux and the progress of the reaction was monitored by
Analytical TLC was performed on Kieselgel 60 plates
F254 (Merck). The reagents were purchased from Sig-
ma–Aldrich. For workup the solutions were dried
1
HPLC and H NMR spectroscopy. After cooling, the
reaction mixture was washed with saturated NaHSO3
solution, saturated NaHCO3 solution and dried over
MgSO4. After evaporation of the solvent the residue
was purified by column chromatography on silica gel.
1
(MgSO4) and concentrated in vacuo. H NMR spectra
were recorded on a Bruker WP-200 spectrometer. The
chemical shifts are given in d (ppm) and the spin–spin
coupling constants (J) in Hz. HRMS were recorded in
FAB mode (glycerol) on a VG 70HS MS spectrometer.
4.2.1. [5-Bromo-2-(2,3-epoxypropenyloxy)phenyl]-acetate
(17). Mp: 44–47 ꢁC 1H NMR: d (ppm): 2.3 (3H, s, CH3),
2.70 (1H, dd, J = 2.63 and 4.87, CH2A); 2.87 (1H, t,
J = 4.87, CH2B); 3.28 (1H, m, CH); 3.88 (1H, dd,
J = 5.73 and 11.19, OCH2A); 4.24 (1H, dd, J = 2.63
and 11.19, OCH2B); 6.85 (1H, d, J = 8.74, H-6); 7.0–
7.13 (2H, m, H-5, H-3). HRMS m/z 285.9843 (calcd
for C11H11BrO4: 285.9841).
4.1. General procedure for the preparation of 15 and 16
To the stirred solution of the substituted 1-(2-hydroxy-
phenyl)ethanones (42 mmol) in dry DMF (80 cm3)
7.3 g K2CO3 and 4.4 cm3 allyl bromide were added
and stirring was continued for 24 h at 80 ꢁC. The reac-
tion mixture was then poured into 10washed with water,
and dried.
4.2.2. [4-Bromo-2-(2,3-epoxypropenyloxily)phenyl]-ace-
1
tate (18). Yield: 71%, yellow oil, H NMR: d (ppm):
Table 3. Study of GP inhibitor activities of 2.3-dihydrobe-
nyo[1,4]dioxin derivatives 44–59
2.3 (3H, s, CH3), 2.68 (1H, dd, J = 2.63 and 4.86,
CH2A); 2.85 (1H, t, J = 4.61, CH2B); 3.29 (1H, m,
CH); 3.95 (1H, dd, J = 5.6 and 11.2, OCH2A); 4.24
(1H, dd, J = 2.8 and 11.2, OCH2B); 6.84 (1H, d,
J = 8.74, H-3); 7.18 (1H, d, J = 2.34, H-6); 7.27 (1H,
dd, J = 2.34 and 8.74, H-4). HRMS m/z 285.9839 (calcd
for C11H11BrO4: 285.9841).
Entry
Ki (GPa)
Ki (GPb)
IC50
1
2
44a
45
—
—
—
80 lM
—
—
—
3
46a
47
—
—
—
4
10 lM
—
—
12 lM
—
—
5
48b
—
6
49
2 mM
—
—
4.3. General procedure for the preparation of 19 and 20
7
50a
51a
52
—
—
—
—
8
To the stirred solution of epoxyacetates (17 and 18) in
dry methanol, 1 equiv of NaOMe was added. The pro-
gress of the reaction was monitored by TLC. The reac-
tion mixture was acidified with aqueous HCl solution,
extracted with CH2Cl2, washed with saturated NaHCO3
solution, and dried. Following evaporation, the residue
was purified by column chromatography on silica gel.
9
9 lM
—
—
30 lM
—
—
—
—
10
11
12
13
14
15
16
17
53a
54
55b
56a
37
7 mM
—
—
—
—
—
—
—
—
—
—
550 lM
>5 mM
>5 mM
560 lM
38
58
—
—
—
—
59
4.3.1. 7-Bromo-2-hydroxymethyl-2,3-dihydrobenzo[1,4]-
dioxin (19). Yield: 65%; mp: 54–57 ꢁC, 1H NMR: d
(ppm): 2.21 (1H, br s, OH); 3.7–4.4 (5H, m,); 6.27
a Insoluble.
b
ꢀ20% inhibition at 625 lM concentration.

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L. Juhasz et al. / Bioorg. Med. Chem. 15 (2007) 4048–4056
4052
(1H, d, J = 8.59, H-5); 6.95 (1H, dd, J = 2.3 and 8.59, H-
6); 7.03 (1H, d, J = 2.3, H-8). HRMS m/z 243.9733
(calcd for C9H9BrO3: 243,9735).
idue (31) was dissolved in dry acetone (75 cm3). Ethyl
1,2-dibromopropionate (20 g, 77 mmol) and K2CO3
were added and the reaction mixture was refluxed for
2 days. After filtration, acetone was evaporated and
the residue was suspended with water. The suspension
was extracted with the mixture of hexane and diethyl
ether (ratio: 1:3; 5 · 25 cm3) and dried. Evaporation of
the solvent furnished a brown syrup which was purified
by vacuum distillation (12.2 g; 58%; bp: 50–70 ꢁC/0.5–
4.3.2. 6-Bromo-2-hydroxymethyl-2,3-dihydrobenzo[1,4]-
1
dioxin (20). Yield: 45%; mp: 104–106 ꢁC; H NMR: d
(ppm): 1.94 (1H, s, OH); 3.7–4.4 (5H, m); 6.78 (1H, d,
J = 8.56, H-8); 6.94 (1H, dd, J = 2.23 and 8.56, H-7);
7.03 (1H, d, J = 2.23, H-5). HRMS m/z 243.9732 (calcd
for C9H9BrO3: 243,9735).
1
1.5 Hgmm). H NMR: d (ppm): 1.25 (3H, t, J = 7.01,
CH3); 4.0–4.4 (4H, m, OCH2 and 3-CH2); 4.55 (1H, t,
J = 3.5, H-2); 5.75 (2H, s, OCH2O); 6.35 and 6.45 (2H,
s, H-5 and H-8). HRMS m/z 252.0633 (calcd for
C12H12O6: 252.0634).
4.3.3. 6,7-Dibromo-2-acetoxymethyl-2,3-dihydrobenzo-
[1,4]dioxin (22). To a stirred solution of 2130 (3.2 g,
19.2 mmol) and AlCl3 (200 mg) in acetic acid (50 cm3),
a solution of bromine (7.79 g, 48 mmol) in acetic acid
(100 cm3) was dropwise added at 0 ꢁC and the mixture
was stirred for eight hours. Then the reaction mixture
was diluted with water and the precipitation filtered
off. The product was washed with aqueous solutions of
NaHSO3 and NaHCO3. Crystallization from methanol
gave 22, as white crystals (3.27 g, 53%, mp: 83–86 ꢁC).
4.3.7. 6,7-Methylenedioxy-2-hydroxymethyl-2,3-dihydro-
benzo[1,4]dioxin (33). To the stirred suspension of
LiAlH4 (0.9 g, 24 mmol) in dry ether (30 cm3), a solution
of 32 (5 g, 20 mmol) in dry ether (20 cm3) was added
dropwise during 30 min under nitrogen at room temper-
ature. Then ethyl acetate and diluted H2SO4 were added
to the reaction mixture (pH 4), the organic layer was
separated, washed with water, and dried. After evapora-
tion the residue was crystallized (3.7 g, 88%, 99–101 ꢁC).
1H NMR: d (ppm): 1.20 ppm (1H, s, OH); 3.60–4.20
(5H, m; H-2, CH2, O–CH2–); 5.80 (2H, s, O–CH2–O);
6.35 (2H, s, H-5 and H-8). HRMS m/z 210.0525 (calcd
for C10H10O5: 210.0528).
1H NMR: d (ppm): 2.1 (3H, s, CH3CO); 4.02 (1H, dd,
J = 6.78 and 11.54); 4.22–4.44 (4H, m); 7.15 (1H, s, H-
5); 7.18 (1H, s, H-8). HRMS m/z 363.8948 (calcd for
C11H10Br2O4: 363.8946).
4.3.4. 6,7-Dibromo-2-hydroxymethyl-2,3-dihydrobenzo-
[1,4]dioxin (23). To a stirred solution of 22 (3.27g,
8.9 mmol) in dry methanol (120 cm3), 1 ml of 1 M
NaOMe was added at room temperature and stirred
for 40 min. Subsequently the reaction mixture was
acidified, diluted with water, extracted with ethyl ace-
tate, and the organic layer was washed with saturated
NaHCO3 solution and dried. After evaporation of the
solvent the residue was crystallized from hexane
(2.48 g, 85%, mp: 88–90 ꢁC). 1H NMR: d (ppm):
1.87 (1H, s, OH); 3.69–4.36 (5H, m); 7.15 (1H, s, H-
5); 7.16 (1H, s, H-8). HRMS m/z 321.8837 (calcd
for C9H8Br2O3: 321.8840).
4.4. General procedure for the preparation of 24–28
To the stirred solution of the alcohols (7.36 mmol) in
dry pyridine (25 cm3) 1.6 g of 4-methylbenzenesulfonyl
chloride (TsCl) was added and the mixture was stirred
at room temperature for 12 h. Then the reaction mixture
was poured into the mixture of crashed ice and diluted
HCl. The precipitated product was filtered off, washed
with water, and dried.
4.4.1. 7-Bromo-2-toluenesulfonyloxymethyl-2,3-dihydro-
benzo[1,4]dioxin (24). Yield: 73%; mp: 78–83 ꢁC; 1H
NMR: d (ppm): 2.47 (3H, s, CH3); 3.95–4.45 (5H, m,
H-2, CH2, O–CH2–); 6.98 (1H, s, H-5); 7.09 (1H, s, H-
8); 7.38 (2H, d, J = 8.15, H-tosyl); 7.65 (2H, d,
J = 8.15, H-tosyl). HRMS m/z 397.9827 (calcd for
C16H15BrO5S: 397.9824).
4.3.5. 2-Hydroxy-4,5-methylenedioxybenzaldehyde (30).
To a stirred solution of 29 (1.4 g, 10 mmol) in dry THF
(50 cm3), paraformaldehyde (2.1 g), dry magnesium
chloride (1.4 g) and triethylamine (3.5 cm3) were added.
The reaction mixture was stirred at room temperature
for 1 h and then boiled under reflux for two hours.
The reaction mixture was poured onto water, acidified
with 10% aqueous HCl solution. The organic layer
was separated and the inorganic layer extracted with
ethyl acetate (3 · 20 cm3). The organic layer was washed
with water and dried. Following evaporation the residue
was purified by column chromatography (eluent: hex-
ane/ethyl acetate = 3:1) to give brown crystals (675 mg,
4.4.2. 6-Bromo-2-toluenesulfonyloxymethyl-2,3-dihydro-
1
benzo[1,4]dioxin (25). Yield: 85%; mp: 103–105 ꢁC; H
NMR: d (ppm): 2.43 (3H, s, CH3); 3.91–4.4 (5H, m,
H-2, CH2, O–CH2–); 6.64 (1H, d, J = 8.54, H-8); 6.89
(1H, dd, J = 2.27 and 8.54, H-7); 6.95 (1H, d, J = 2.27,
H-5); 7.34 (2H, d, J = 8.33, H-tosyl); 7.74 (2H, d,
J = 8.33, H-tosyl). HRMS m/z 397.9827 (calcd for
C16H15BrO5S: 397.9824).
1
36%; mp: 125–127 ꢁC). H NMR: d (ppm): 6.01 (2H,
s, O–CH2–O); 6.46 (1H, s, H-5); 6.86 (1H, s, H-8);
9.62 (1H, s, CHO); 11.79 (1H, s, OH). HRMS m/z
166.0264 (calcd for C8H6O4: 166.0266).
4.4.3. 6,7-Dibromo-2-toluenesulfonyloxymethyl-2,3-dihy-
1
drobenzo[1,4]dioxin (26). Yield: 87%; mp: 94–97 ꢁC; H
4.3.6. Ethyl 6,7-methylenedioxy-2,3-dihydrobenzo[1,4]-
dioxin-2-carboxylate (32). To a stirred suspension of 30
(11.5 g, 66 mmol) in dry triethylamine (100 cm3),
18 cm3, of 30% H2O2 was added dropwise during 1 h
at 0 ꢁC. The mixture was then concentrated and the res-
NMR: d (ppm): 2.47 (3H, s, CH3); 3.92–4.42 (5H, m,
H-2, CH2, O–CH2–); 6.98 (1H, s, H-8); 7.09 (1H, H-
5); 7.34 (2H, d, J = 8.34, H-tosyl); 7.76 (2H, d,
J = 8.34, H-tosyl). HRMS m/z 475.8927 (calcd for
C16H14Br2O5S: 475.8929).

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4053
4.4.4. 2-Toluenesulfonyloxymethyl-2,3-dihydrobenzo[1,4]-
dioxin (27). Yield: 80%; mp: 71–73 ꢁC; 1H NMR: d
(ppm): 2.44 (3H, s, CH3); 3.9–4.41 (5H, m, H-2, CH2,
O–CH2–); 6.62–6.98 (5H, m, AR–H); 7.32 (2H, d,
J = 8.28, H-tosyl); 7.76 (2H, d, J = 8.28, H-tosyl).
HRMS m/z 320.0715 (calcd for C16H16O5S: 320.0718).
CHO). HRMS m/z 270.0887 (calcd for C16H14O4:
270.0892).
4.5.6. 4-(7-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-ylmeth-
oxy)-3-methoxybenzaldehyde (39). Yield: 90.7%; mp: 88–
90 ꢁC; 1H NMR: d (ppm): 3.91 (3H, s, OCH3), 4.24–4.64
(5H, m); 6.77 (1H, d, J = 8.62, H-5); 6.96 (1H, dd,
J = 2.22 and 8.62, H-6); 7.01 (1H, d, J = 7.99, H-40),
7.06 (1H, d, J = 2.2, H-8); 7.42–7.45 (2H, m, H-20, H-
60); 9.86 (1H, s, CHO). HRMS m/z 378.0105 (calcd for
C17H15BrO5: 378.0103).
4.4.5. 6,7-Methylenedioxy-2-toluenesulfonyloxymethyl-
2,3-dihydrobenzo[1,4]dioxin (28). Yield: 92%; mp: 97–
98 ꢁC; 1H NMR: d (ppm): 2.45 (3H, s, CH3); 3.90–
4.40 (5H, m, H-2, CH2, O–CH2–); 5.80 (2H, s, O–
CH2–O); 6.28 and 6.34 (2H, s, H-5 and H-8); HRMS
m/z 364.0619 (calcd for C17H16O7S: 364.0617).
4.5.7. 4-(6-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-ylmeth-
oxy)-3-methoxybenzaldehyde (40). Yield: 95%; mp: 129–
1
4.5. General procedure for the preparation of 34–43
129 ꢁC; H NMR: d (ppm): 3.95 (3H, s, OCH3), 4.16–
4.46 (4H, m); 4.53–4.68 (1H, m); 6.77 (1H, d,
J = 8.57), 6.91–7.06 (3H, m); 7.38–7.46 (2H, m); 9.9
(1H, s, CHO). HRMS m/z 378.0106 (calcd for
C17H15BrO5: 378.0103).
The mixture of the tosylates 24–28 (6.25 mmol),
8.2 mmol of the hydroxyaldehyde, and 1,6 g K2CO3 in
dry DMF (50 cm3) was stirred at 80 ꢁC. The progress
of reaction was monitored by TLC (toluene/ethyl ace-
tate = 4:1). Subsequently the reaction mixture was
poured into cold water and extracted with ether. The or-
ganic phase was washed with aqueous NaHCO3 solution
and dried. After evaporation the residue was purified by
column chromatography.
4.5.8. 4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]diox-
in-2-ylmethoxy)-3-methoxybenzaldehyde (41). Yield: 99%;
mp: 138–139 ꢁC; 1H NMR: d (ppm): 3.91 (3H, s,
CH3O); 4.1–4.7 (5H, m); 5.85 (2H, s, O–CH2–O);
6.43 (1H, s, H-5); 6.45 (1H, s, H-8); 6.99 (1H, d, J = 8.6,
H-50); 7.38–7.46 (2H, m, H-20, H-60); 9.85 (1H, s,
CHO). HRMS m/z 344.0893 (calcd for C18H16O7:
344.0896).
4.5.1. 4-(7-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-ylmeth-
1
oxy)-benzaldehyde (34). Yield: 85.2%; mp: 86–88 ꢁC; H
NMR: d (ppm): 4.2–4.6 (5H, m); 6.77 (1H, d, J = 8.62,
H-5); 6.96 (1H, dd, J = 2.22 and 8.62, H-6); 7.03 (2H,
d, J = 8.7, H-30, H-40), 7.06 (1H, d, J = 2.2, H-8); 7.85
(2H, d, J = 8.7, H-20, H-60); 9.89 (1H, s, CHO). HRMS
m/z 347.9999 (calcd for C16H13BrO4: 347.9997).
4.5.9. 4-(6,7-Dibromo-2,3-dihydrobenzo[1,4]dioxin-
2-ylmethoxy)-3-methoxybenzaldehyde (42). Yield: 72.5%;
mp: 127–129 ꢁC; H NMR: d (ppm): 3.92 (3H, OCH3);
4.19–4.48 (4H, m); 4.56–4.68 (1H, m); 7.00 (1H, d,
J = 8.57, H-50), 7.17 (1H, s, H-5) 7.18 (1H, s, H-8);
7.41–7.48 (2H, m; H-20 and H-60); 9.87 (1H, s,
CHO). HRMS m/z 455.9206 (calcd for C17H14Br2O5:
455.9208).
1
4.5.2. 4-(6-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-ylmeth-
oxy)-benzaldehyde (35). Yield: 97%; mp: 126–129 ꢁC; 1H
NMR: d (ppm): 4.1–4.66 (5H, m); 6.77 (1H, d, J = 8.65,
H-8); 6.96 (1H, dd, J = 2.4 and 8.65, H-7); 7.03 (2H, d,
J = 8.46, H-30, H-50), 7.04 (1H, d, J = 2.4, H-8); 7.84
(2H, d, J = 8.46, H-20, H-60); 9.88 (1H, s, CHO). HRMS
m/z 347.999 (calcd for C16H13BrO4: 347.9997).
4.5.10. 4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-3-
methoxybenzaldehyde (43). Yield: 85%; mp: 73–75 ꢁC;
1H NMR: d (ppm): 3.92 (3H, s, CH3O); 4.16–4.73
(5H, m); 6.78–6.95 (4H, m, H-5, H-6, H-7,H-8); 7.02
(1H, d, J = 8.7, H-50); 7.38–7.51 (2H, m, H-20, H-60);
9.86 (1H, s, CHO). HRMS m/z 300.0996 (calcd for
C17H16O5: 300.0998).
4.5.3. 4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]diox-
in-2-ylmethoxy)-benzaldehyde (36). Yield: 85%; mp:
1
160–161 ꢁC; H NMR: d (ppm): 4.1–4.4 (4H, m); 4.5–
4.65 (1H, m); 5.85 (2H, s, O–CH2–O); 6.47 (1H, s, H-
5); 6.48 (1H, s, H-8); 7.0 (2H, d, J = 8.73, H-30, H-50);
7.9 (2H, d, J = 8.73, H-20, H-60); 9.9 (1H, s, CHO).
HRMS m/z 314.0791 (calcd for C17H14O6: 314.0790).
4.6. General procedure for the preparation of 44–53
A mixture of the aldehyde 34–43 (20 mmol) thiazolidine-
2.4-dione (22 mmol), and sodium acetate was heated at
140 ꢁC for 2 h without solvent. Then water was added
to the reaction mixture, the solid product was filtered
off, washed with chloroform for the removal of the ex-
cess of thiazolidine-2.4-dione, and dried.
4.5.4. 4-(6,7-Dibromo-2,3-dihydrobenzo[1,4]dioxin-2-
ylmethoxy)-benzaldehyde (37). Yield: 90%; mp: 117–
120 ꢁC; 1H NMR: d (ppm): 4.09–4.7 (5H, m); 7.02
(2H, d, J = 8.75; H-30, H-50); 7.17 (1H, s, H-5); 7.18
(1H, s, H-8); 7.85 (2H, d, J = 8.75, H-20, H-60); 9.9
(1H, s, CHO). HRMS m/z 425.9097 (calcd for
C16H12Br2O4: 425.9102).
4.6.1. 5-[4-(7-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-ylmeth-
oxy)-benzylidene]-thiazolidine-2,4-dione (44). Yield: 80%;
mp: 208–211 ꢁC; 1H NMR (DMSO): d (ppm): 4.06–
4.73 (5H, m); 5.88 (1H, d, J = 8.57, H-5); 7.02 (1H,
dd, J = 2.29 and 8.57, H-6); 7.13 (1H, d, J = 2.29,
H-8); 7.14 (2H, d, J = 8.8, H-30, H-50); 7.59 (2H, d,
J = 8.8, H-20, H-60); 7.76 (1H, s, CH). HRMS m/z
446.9778 (calcd for C19H14BrNO5S: 446.9776).
4.5.5. 4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-benz-
1
aldehyde (38). Yield: 85%; mp: 60–62 ꢁC; H NMR: d
(ppm): 4.12–4.48 (4H, m); 4.49–4.65 (1H, m); 6.8–6.96
(4H, m, H-50–H-80); 7.0 ppm (2H, d, J = 8.75, H-30,
H-50); 7.83 (2H, d, J = 8.75, H-20, H-60); 9.87 (1H, s,

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4054
4.6.2. 5-[4-(6-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-yl-
methoxy)-benzylidene]-thiazolidine-2,4-dione (45). Yield:
80%; mp: 187–189 ꢁC; 1H NMR (DMSO): d (ppm):
4.1–4.75 (5H, m); 6.92 (1H, d, J = 8.52, H-8), 7.06
(1H, dd, J = 2.12 and 8.52, H-7), 7.17 (1H, d, J = 2.12,
H-5); 7.2 (2H, d, J = 8.64, H-30, H-50); 7.61 (2H, d,
J = 8.64, H-20, H-60); 7.8 (1H, s, CH); 12.56 (1H, s,
NH). HRMS m/z 446.9775 (calcd for C19H14BrNO5S:
446.9776).
4.6.9. 5-[4-(6,7-Dibromo-2,3-dihydrobenzo[1,4]dioxin-2-
ylmethoxy)-3-methoxy-benzylidene]-thiazolidine-2,4-dione
(52). Yield: 61%; mp: 170–172 ꢁC; 1H NMR (DMSO): d
(ppm): 3.74 (3H, s, OCH3); 4.2–4.7 (5H, m); 7.14 (2H, s,
H-20, H-60); 7.22 (1H, s, H-50), 7.37 (1H, s, H-50); 7.39
(1H, s, H-80); 7.46 (1H, s, CH). HRMS m/z 554.8985
(calcd for C20H15Br2NO6S: 554.8987).
4.6.10. 5-[4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-
3-methoxy-benzylidene]-thiazolidine-2,4-dione (53). Yield:
1
65%; mp: >230 ꢁC (decomposed); H NMR (DMSO): d
4.6.3. 5-[4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]di-
oxin-2-ylmethoxy)-benzylidene]-thiazolidine-2,4-dione (46).
Yield: 63%; mp: >300 ꢁC; 1H NMR (DMSO): d
(ppm): 4.0–4.6 (5H, m); 5.93 (2H, s, O–CH2–O);
6.61 (1H, s, H-5); 6.64 (1H, s, H-8); 6.63 (2H, d,
J = 8.66, H-30, H-50); 7.49 (1H, s, CH); 7.91 (2H, d,
J = 8.66, H-20, H-60). HRMS m/z (calcd for
C20H15NO7S: 413.0569).
(ppm): 3.83 (3H, s, OCH3); 4.1–4.7 (5H, m); 6.7–7.0
(4H, m, H-5–H-8); 7.1–7.2 (3H, 3, H-20, H-50, H-60);
7.49 (1H, s, CH). HRMS m/z 399.0780 (calcd for
C20H17NO6S: 399.0777).
4.7. General procedure for the preparation of 54–57
Five hundred milligrams of the benzylidene derivatives
46, 48, 51, and 53 hydrogenated in acetic acid
(300 cm3) in the presence of Pd(C) (300 mg) at 12 atm
pressure until the level of the pressure was stabilized.
Then the catalyst was filtered off and the pure product
was isolated after evaporation of the solvent.
4.6.4. 5-[4-(6,7-Dibromo-2,3-dihydrobenzo[1,4]dioxin-2-
ylmethoxy)-benzylidene]-thiazolidine-2,4-dione (47). Yield:
1
60%; mp: >250 ꢁC (decomposed); H NMR (DMSO): d
(ppm): 4.2–4.8 (5H, m); 7.08 (2H, d, J = 8.65, H-30, H-
50); 7.28 (1H, s, CH); 7.37 (1H, s, H-5); 7.40 (1H, s,
H-8); 7.50 (2H, d, J = 8.65, H-20, H-30). HRMS m/z
542.8885 (calcd for C19H13Br2NO5S: 524.8881).
4.7.1. 5-[4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]-
dioxin-2-ylmethoxy)-benzyl]-thiazolidine-2,4-dione (54).
Yield: 86%; mp: >300 ꢁC; 1H NMR (DMSO): d
(ppm): 2.62 (1H, dd, J = 10.36 and 13.84, CH2A); 3.35
(1H, dd, J = 3.56 and 13.84, CH2B); 4.1–4.7 (6H, m);
5.89 (2H, s, O–CH2–O); 6.56 (1H, s, H-50); 6.59 (1H,
s, H-80); 6.83 (2H, d, J = 8.57, H-30, H-50); 7.13 (2H,
d, J = 8.57, H-20, H-60). HRMS m/z 415.0722
(C20H17NO7S: 415.0726).
4.6.5. 5-[4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-
benzylidene]-thiazolidine-2,4-dione (48). Yield: 57%; mp:
1
226–228 ꢁC; H NMR (DMSO): d (ppm): 4.0–4.3 (5H,
m); 6.72–6.96 (4H, m); 7.13 (2H, d, J = 8.72, H-30, H-
50); 7.58 (2H, d, J = 8.72, H-20, H-60); 7.75 (1H, s,
CH). HRMS m/z 369.0673 (calcd for C19H15NO5S:
369.0671).
4.7.2. 5-[4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-
benzyl]-thiazolidine-2,4-dione (55). Yield: 78%; mp:
154–156 ꢁC; 1H NMR (DMSO): d (ppm): 3.05 (1H,
dd, J = 8.87 and 14.01, CH2A); 3.35 (1H, dd, J = 4.04
and 14.01, CH2B); 4.05–4.62 (6H, m); 4.86 (1H, dd,
J = 4.04 and 8.87, CH) 6.77–6.98 (6H, m); 7.17 (2H, d,
J = 8.62; H-20, H-60). HRMS m/z 371.0824 (calcd for
C19H17NO5S: 371.0827).
4.6.6. 5-[4-(7-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-yl-
methoxy)-3-methoxy-benzylidene]-thiazolidine-2,4-dione
(49). Yield: 57%; mp: >230 ꢁC (decomposed); 1H
NMR (DMSO): d (ppm): 3.79 (3H, s, OCH3), 4.08–
4.8 (5H, m); 6.87 (1H, d, J = 8.64, H-5); 6.99 (1H,
dd, J = 2.21 and 8.64, H-6); 7.01 (2H, m); 7.13 (1H,
d, J = 2.21, H-8); 7.16 (1H, s); 7.25 (1H, s, CH).
HRMS m/z 476.9884 (calcd for C20H16BrNO6S:
476.9882).
4.7.3. 5-[4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]-
dioxin-2-ylmethoxy)-3-methoxy-benzyl]-thiazolidine-2,4-
dione (56). Yield: 65%; mp: 160–163 ꢁC; 1H NMR
(DMSO): d (ppm): 3.04 (1H, dd, J = 9.38 and 14.02,
CH2A); 3.33 (1H, dd, J = 4.28 and 14.02, CH2B); 3.74
(3H, s, OCH3); 3.96–4.51 (5H, m); 4.90 (1H, dd,
J = 4.28 and 9.38, CH); 5.88 (2H, s, O–CH2–O); 6.56
(1H, s, H-5); 6.59 (1H, s, H-8); 6.72 (1H, dd, J = 1.56
and 8.18; H-60); 6.89 (1H, d, J = 1.56, H-20); 6.93 (1H,
d, J = 8.18, H-50). HRMS m/z 445. 0829 (calcd for
C21H19NO8S: 445.0831).
4.6.7. 5-[4-(6-Bromo-2,3-dihydrobenzo[1,4]dioxin-2-yl-
methoxy)-3-methoxy-benzylidene]-thiazolidine-2,4-dione
(50). Yield: 89%; mp: 197–199 ꢁC; 1H NMR (DMSO): d
(ppm): 3.87 (3H, s, OCH3); 4.1–4.7 (5H, m); 6.91 (1H, d,
J = 8.62, H-8); 7.04 (1H, dd, J = 2.23 and 8.62, H-7);
7.12 (2H, s, H-20, H-60); 7.15 (1H, d, J = 2.23, H-5);
7.37 (1H, s, CH). HRMS m/z 476.9884 (calcd for
C20H16BrNO6S: 476.9882).
4.6.8. 5-[4-(6,7-Methylenedioxy-2,3-dihydrobenzo[1,4]di-
oxin-2-ylmethoxy)-3-methoxy-benzylidene]-thiazolidine-
2,4-dione (51). Yield: 84%; mp: 174–176 ꢁC; H NMR
(DMSO): d (ppm): 3.83 (3H, s, OCH3); 4.0–4.6 (5H,
m); 5.93 (2H, s, O–CH2–O); 6.61 (1H, s, H-5); 6.63
(1H, s, H-5); 7.1 (2H, s, H-20, H-60); 7.2 (1H, s, H-50);
7.3 (1H, s, CH). HRMS m/z 443.0678 (calcd for
C21H17NO8S: 443.0675).
4.7.4. 5-[4-(2,3-Dihydrobenzo[1,4]dioxin-2-ylmethoxy)-3-
methoxy-benzyl]-thiazolidine-2,4-dione (57). Yield: 65%;
mp: 115–120 ꢁC (decomposed); H NMR (DMSO): d
(ppm): 3.1 (1H, dd, J = 9.7 and 14.4, CH2A); 3.48 (1H,
dd, J = 3.78 and 14.4, CH2B); 3.85 (3H, s, OCH3); 4.1–
4.7 (6H, m); 6.7–7.3 (7H, m). HRMS m/z 401.0935
(calcd for C20H19NO6S: 401.0933).
1
1

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L. Juhasz et al. / Bioorg. Med. Chem. 15 (2007) 4048–4056
4055
8. Kuhn, B.; Hilpert, H.; Benz, J.; Binggeli, A.; Grether, U.;
Humm, R.; Ma¨rki, H. P.; Meyer, M.; Mohr, P. Bioorg.
Med. Chem. Lett. 2006, 16, 4016.
9. Watson, K. A.; Chrysina, E. D.; Tsitsanou, K. E.;
Zographos, S. E.; Archontis, G.; Fleet, G. W. J.; Oiko-
nomakos, N. G. Proteins Struct. Funct. Bioinformatics
2005, 966.
4.7.5. 2-Phenoxymethyl-2,3-dihydrobenzo[1,4]dioxin (58).
The mixture of 27 (500 mg, 1.5 mmol), phenol (200 mg),
and K2CO3 (300 mg) in dry DMF (20 cm3) was stirred
at 80 ꢁC. The progress of reaction was monitored by
TLC (toluene/ethyl acetate = 4:1). The reaction mixture
was poured into cold water and extracted with ether, the
organic phase was washed with aqueous NaHCO3 solu-
tion and dried. Following evaporation of the solvent the
residue was purified by column chromatography to ob-
tain 58 as white crystals (124 mg, 35%, mp: 35–37 ꢁC).
1H NMR (CDCl3): d (ppm): 4.0–4.72 (5H, m); 6.66–
7.08 (7H, m); 7.19–7.44 (2H, m). HRMS m/z 242.0945
(C15H14O3: 242.0943).
´
´
10. Somsak, L.; Nagy, V.; Docsa, T.; Toth, B.; Gergely, P.
Tetrahedron Asymmetry 2000, 11, 405.
´
´
´
´
11. Czifrak, K.; Kovacs, L.; Ko¨ver, E. K.; Somsak, L.
Carbohydr. Res. 2005, 340, 2328.
12. Anagnostou, E.; Kosmopoulou, M. N.; Chrysina, E. D.;
Leonidas, D. D.; Hadjiloi, T.; Tiraidis, C.; Zographos, S.
´
´
E.; Gyo¨rgydeak, Z.; Somsak, L.; Docsa, T.; Gergely, P.;
Kolisis, F. N.; Oikonomakos, G. N. Bioorg. Med. Chem.
2006, 14, 181.
4.7.6. 6,7-Dibromo-2-phenoxymethyl-2,3-dihydro-benzo-
[1,4]dioxin (59). The mixture of 26 (200 mg, 0.42 mmol),
phenol (60 mg, 0.63 mmol), and 710 mg of K2CO3 in
dry DMF (10 cm3) was stirred at 80 ꢁC. The progress
of reaction was monitored by TLC (toluene/ethyl ace-
tate = 4:1). Subsequently the reaction mixture was
poured into cold water and extracted with ether. The
organic phase was washed with aqueous NaHCO3
solution and dried. After evaporation, the residue was
purified by column chromatography to yield 59 as
white crystals (131.5 mg, 79%, mp: 78–84 ꢁC). 1H
NMR (CDCl3): d (ppm): 4.03–4.58 (5H, m); 6.8–7.0
(3H, m, Ar–H); 7.14 (1H, s, H-5); 7.15 (1H, s, H-8);
7.22–7.33 (2H, H, Ar–H). HRMS m/z (calcd for
C15H12Br2O3: 397.9153).
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The authors thank the National Science Foundation
(F-047025, T-049436 and NL61336) for valuable finan-
´
´
cial support and Laszlo Juhasz is indebted to the Minis-
try of Education for the Bekesy Gyo¨rgy Postdoctoral
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