Synthesis of thioflavanone and flavanone derivatives by cyclization of chalcones

Article abstract of DOI:10.1055/s-0029-1216791

Chalcones bearing suitably positioned protected 2′-sulfanyl or 6′-hydroxy groups cyclize to form the corresponding thioflavanones and flavanones, respectively. The thioflavanones were prepared by a new method involving deprotection of the sulfanyl group u

Full text of DOI:10.1055/s-0029-1216791

PAPER
1811
Synthesis of Thioflavanone and Flavanone Derivatives by Cyclization of
Chalcones
T
hioflavanones and Flav
o
anones byC
j
yclizat
c
ionof
C
ha
l
i
cones ech Konieczny,* Marek Konieczny
Department of Organic Chemistry, Medical University of Gdaꢀsk, 80-416 Gdaꢀsk, Poland
Fax +48(58)3493145; E-mail: wkonieczny@amg.gda.pl
Received 31 December 2008
(Scheme 1, X = CH2-4-MeOC6H4). Deprotection and
subsequent cyclization were performed as a one-pot reac-
tion in the presence of formic acid.10,11 The reaction con-
ditions were found to be inappropriate for synthesis of 5-
Abstract: Chalcones bearing suitably positioned protected 2¢-sul-
fanyl or 6¢-hydroxy groups cyclize to form the corresponding
thioflavanones and flavanones, respectively. The thioflavanones
were prepared by a new method involving deprotection of the sul-
fanyl group under alkaline conditions. These reactions provide a methoxythioflavanones, because the methoxy group was
partially cleaved in the presence of formic acid.12
route to new biologically interesting molecules.
However, 5-methoxy derivatives could be prepared if sil-
ver nitrate in ethanol was used to deprotect the 4-methox-
ybenzyl sulfides.12 The Taylor–Dean method is acid
specific, and replacement of the formic acid with trifluo-
roacetic acid led to thioaurones.10
Key words: chalcone cyclization, thioflavanone synthesis, benz-
oxathiolone ring opening, flavanones
Flavonoids are a well-known source of inspiration in the
search for new medicines.1 Surprisingly, however, the bi-
ological activity of their sulfur analogues has been rela-
tively little explored,2–8 even though it has been found that
replacement of the oxygen atom by sulfur does not de-
prive the compounds of activities,3a,6,8 and sometimes can
even improve it.
To overcome the problems associated with the Taylor–
Dean acid-induced deprotection–cyclization sequence,
we examined the use of thiophenols protected with base-
cleavable groups. We report the synthesis of thiofla-
vanones 2 from chalcones 1 (Scheme 2), which can be
conveniently obtained13 from 4-acetyl-5-methoxy-1,3-
benzoxathiol-2-one. Treatment of chalcones 1a–c with
sodium hydroxide in aqueous ethanol gave the 8-hy-
droxythioflavanone derivatives 2a–c, respectively
(Table 1, entries 1–3). Alternatively, the transformation
could be achieved with amines (preferably piperidine) in
chloroform (entries 4–6). The second approach appears to
be more convenient, especially if protection of the newly
formed 8-hydroxy group with a base-cleavable group is
required. A suitable method of cleavage of the piperidin-
1-ylcarbonyl (PPCO) group has already been described.14
There are two general methods for the synthesis of thiofla-
vanone derivatives (Scheme 1).
SH
R2
+
R3O
R1
path A
path B
S
O
R2
X
S
R1
O
R2
O
X
X
O
RO
R1
S
OH– in EtOH
S
O
or amine in CHCl3
Scheme 1 General methods for the synthesis of thioflavanones
MeO
O
MeO
O
1
The first method (path A) is by far the most popular, and
depends on the Michael addition of a thiophenol to a suit-
able cinnamic acid derivative, followed by Friedel–Crafts
cyclization.2,4,9 The second method (path B) involves in-
tramolecular ring closure to form the thiopyranone ring,
and closely resembles the synthesis of flavanones from 2¢-
hydroxychalcones. The approach has been converted into
a practical synthetic method by Taylor and Dean,
who used S-(4-methoxybenzyl)-protected substrates
2
BF3⋅SMe2
in CH2Cl2
O
X
O
O
S
X
H+ in AcOH
O
O
S
O
HO
O
4
3
SYNTHESIS 2009, No. 11, pp 1811–1814
Advanced online publication: 04.05.2009
DOI: 10.1055/s-0029-1216791; Art ID: P15308SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
9
Scheme 2 Synthesis of thioflavanones 2, chalcones 3, and flava-
nones 4

1812
W. Konieczny, M. Konieczny
PAPER
Table 1 Synthesis of Thioflavanones 2
Cond.a Product
spectra were recorded on a 500-MHz spectrometer (Varian Unity
Plus). Elemental analyses were performed on a Carlo-Erba 1108 in-
strument.
Entry Substrate
Yield
(%)
8-Hydroxy-5-methoxy-2-phenyl-2,3-dihydro-4H-1-benzothio-
pyran-4-one (2a)
1
2
3
4
5
6
1a (X = H)
A
A
A
B
B
B
2a (X = H; R = H)
50
51
64
70
A suspension of 1,3-benzoxathiol-2-one 1a (X = H; 156 mg, 0.5
mmol) in MeOH (5 mL) was deoxygenated with N2 and mixed with
2 M aq NaOH (2 mL). The mixture was stirred at reflux for 2 h,
cooled, and acidified with 2 M HCl. The resulting precipitate was
filtered off, washed with MeOH, and crystallized [MeO(CH2)2OH]
to give thioflavanone 2a as a yellow solid; yield: 72 mg (50%); mp
206–209 °C.
1b (X = 4-Br)
1c (X = 4-OMe)
1a (X = H)
2b (X = 4-Br; R = H)
2c (X = 4-OMe; R = H)
2d (X = H; R = PPCOb)
1d (X = 4-Cl)
1b (X = 4-Br)
2e (X = 4-Cl; R = PPCOb) 59
2f (X = 4-Br; R = PPCOb) 30
IR (KBr): 3300, 1639, 1573, 1466, 1288, 1246, 1040 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.79 (s, 1 H, OH), 7.47 (d,
J = 7.3 Hz, 2 H, H-2¢, H-6¢), 7.32–7.40 (m, 3 H, H-3¢, H-4¢, H-5¢),
6.96 (d, = 8.8 Hz, 1 H, H-7), 6.74 (d, J = 8.8 Hz, 1 H, H-6), 4.74 (dd,
J1 = 2.9 Hz, J2 = 13.1 Hz, 1 H, H-2), 3.71 (s, 3 H, OCH3), 3.30 (dd,
a A: NaOH, EtOH–H2O; B: piperidine, CHCl3.
b PPCO = piperidin-1-ylcarbonyl.
Interestingly, chalcones 1 can also be transformed into J1 = 13.1 Hz, J2 = 15.1 Hz, 1 H, H-3), 2.93 (dd, J1 = 2.9 Hz,
J2 = 15.1 Hz, 1 H, H-3).
flavanones 4 by a two-step procedure involving deprotec-
tion of the methoxy group with boron trifluoride–dimeth-
yl sulfide complex to give the related hydroxy derivatives
3, which undergo acid-induced cyclization to form the fla-
vanones 4 (Scheme 2). The resulting compounds are list-
ed in Table 2.
Anal. Calcd for C16H14O3S: C, 67.11; H, 4.93; S, 11.20. Found: C,
66.73; H, 4.95; S, 11.05.
2-(4-Bromophenyl)-8-hydroxy-5-methoxy-2,3-dihydro-4H-1-
benzothiopyran-4-one (2b)
A suspension of 1,3-benzoxathiol-2-one 1b (X = 4-Br; 150 mg,
0.383 mmol) in MeOH (4 mL) was deoxygenated with N2 and
mixed with 2 M aq NaOH (2 mL). The mixture was stirred at reflux
for 2 h, cooled, and acidified with dil HCl. The product was extract-
ed with CHCl3 (2 × 30 mL), washed with H2O (3 × 10 mL), and
dried (MgSO4). The solvent was evaporated, and the residue was
crystallized (MeOH) to give thioflavanone 2b as an orange solid;
yield: 71 mg (51%); mp 206–210 °C.
Table 2 Preparation of Hydroxychalcones 3 and Flavanones 4
Entry
Substrate
Cond.a
Product
3a
Yield (%)
1
2
3
4
5
6
7
8
1a (X = H)
A
A
A
A
A
B
B
B
49
78
41
68
42
52
89
50
1b (X = 4-Br)
1c (X = 4-OMe)
1e (X = 4-NO2)
1f (X = 3-Cl)
3a (X = H)
3b
IR (KBr): 3136, 1640, 1570, 1276, 1241, 1042 cm–1.
3c
1H NMR (300 MHz, DMSO-d6): d = 9.83 (s, 1 H, OH), 7.58 (d,
J = 8.5 Hz, 2 H, H-3¢, H-5¢), 7.42 (d, J = 8.5 Hz, 2 H, H-2¢, H-6¢),
6.95 (d, J = 8.9 Hz, 1 H, H-7), 6.74 (d, J = 8.9 Hz, 1 H, H-6), 4.75
(dd, J1 = 12.3 Hz, J2 = 3.3 Hz, 1 H, H-2), 3.70 (s, 3 H, OCH3), 3.23
(dd, J1 = 12.3 Hz, J2 = 15.3 Hz, 1 H, H-3), 2.93 (dd, J1 = 15.3 Hz,
J2 = 3.3 Hz, 1 H, H-3).
3d
3e
4a
3b (X = 4-Br)
3e (X = 3-Cl)
4b
Anal. Calcd for C16H13BrO3S: C, 52.61; H, 3.59; S, 8.78. Found: C,
52.48; H, 3.60; S, 8.63.
4c
a A: BF3·Me2S; B: H2SO4 in AcOH.
8-Hydroxy-5-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-4H-1-
benzothiopyran-4-one (2c)
A suspension of 1,3-benzoxathiol-2-one 1c (X = 4-OMe; 171 mg,
0.5 mmol) in MeOH (5 mL) was deoxygenated with N2, and 2 M aq
NaOH (2 mL) was added. The mixture was stirred at reflux for 2 h,
cooled, and acidified with dil HCl. The resulting precipitate was fil-
tered off, washed with MeOH, and crystallized (MeOH) to give
thioflavanone 2c as an orange solid; yield: 101 mg (64%); mp 197–
201 °C.
These reactions appear to be of interest from the point of
view of medicinal chemistry, as they open a way to fla-
vanones with the same pattern of potential pharmaco-
phores in ring A (two para-positioned oxygen atoms, and
a sulfur atom ortho to one of the oxygens), but with differ-
ent spatial arrangement of the pharmacophoric atoms. In
this context, this is a continuation of our work on similarly
substituted thioaurones.15 Possible modifications of the
pharmacophoric atoms aimed at optimization of such
pharmacologically important parameters as bulkiness, ri-
gidity, lipophilicity, and solubility have already been
demonstrated for thioaurones.14
IR (KBr): 3263, 1643, 1572, 1513, 1256, 1046 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 9.77 (s, OH, 1 H), 7.40 (d,
J = 8.7 Hz, 2 H, H-2¢, H-6¢), 6.93–6.98 (m, 3 H, H-3¢, H-5¢, H-7),
6.74 (d, J = 8.7 Hz, 1 H, H-6), 4.68 (dd, J1 = 3.0 Hz, J2 = 13.0 Hz,
1 H, H-2), 3.76 (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 3.28 (dd,
J1 = 13.0 Hz, J2 = 15.1 Hz, 1 H, H-3), 2.88 (dd, J1 = 3.0 Hz,
J2 = 15.1 Hz, 1 H, H-3).
Anal. Calcd for C17H16O4S: C, 64.54; H, 5.10; S, 10.14. Found: C,
64.43; H, 5.05; S, 10.05.
Melting points are uncorrected. IR spectra were obtained from KBr
pellets by using a Thermo Mattson Satellite instrument. The NMR
Synthesis 2009, No. 11, 1811–1814 © Thieme Stuttgart · New York

PAPER
Thioflavanones and Flavanones by Cyclization of Chalcones
1813
5-Methoxy-4-oxo-2-phenyl-3,4-dihydro-2H-1-benzothiopyran-
8-yl 1-Piperidinecarboxylate (2d)
5-Hydroxy-4-[(2E)-3-phenylprop-2-enoyl]-1,3-benzoxathiol-2-
one (3a)
A suspension of 1,3-benzoxathiol-2-one 1a (X = H; 100 mg, 0.32
mmol) in CH2Cl2 (5 mL) was deoxygenated with N2, and piperidine
(0.3 mL, 3 mmol) was added. The mixture was stirred at r.t. for 1 h
and then concentrated. The residue was crystallized (CHCl3–
MeOH) to give thioflavanone 2d as a colorless solid; yield: 89 mg
(70%); mp 165–166 °C.
Substrate: 1a (X = H); reaction time: 2.5 h; crystallization:
MeO(CH2)2OH; orange solid; yield: 49%; mp 165–168 °C.
IR (KBr): 3292, 1744, 1595, 1551, 1339, 1282, 1047 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.35 (s, 1 H, OH), 8.13 (d,
J = 16.1 Hz, 1 H, H-b), 7.80 (d, J = 16.1 Hz, 1 H, H-a), 7.72 (m, 2
H, H-2¢, H-6¢), 7.60 (d, J = 8.8 Hz, 1 H, H-7), 7.47 (m, 3 H, H-3¢,
H-4¢, H-5¢), 7.08 (d, J = 8.8 Hz, 1 H, H-6).
IR (KBr): 1722, 1670, 1417, 1215 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.48 (d, J = 7.3 Hz, 2 H, H-2¢,
H-6¢), 7.42–7.29 (m, 4 H, H-3¢, H-4¢, H-5¢, H-7), 6.93 (d, J = 9.3
Hz, 1 H, H-6), 4.84 (dd, J1 = 2.9 Hz, J2 = 12.9 Hz, 1 H, H-2), 3.81
(s, 3 H, OCH3), 3.52 (br s, 2 H, piperidine), 3.3–3.4 (m, H-3, pipe-
ridine, H2O), 2.97 (dd, J1 = 2.9 Hz, J2 = 15.6 Hz, 1 H, H-3), 1.43–
1.6 (m, 6 H, piperidine).
Anal. Calcd for C16H10O4S: C, 64.42; H, 3.38; S, 10.75. Found: C,
64.36; H, 3.39; S, 10.76.
4-[(2E)-3-(4-Bromophenyl)prop-2-enoyl]-5-hydroxy-1,3-benz-
oxathiol-2-one (3b)
Substrate: 1b (X = 4-Br); reaction time: 1 h; crystallization:
MeO(CH2)2OH; yellow solid; yield: 78%; mp 153–155 °C.
Anal. Calcd for C22H23NO4S: C, 66.48; H, 5.83; N, 3.52; S, 8.07.
Found: C, 66.22; H, 5.83; N, 3.61; S, 8.04.
IR (KBr): 3280, 1691, 1598, 1428 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.36 (br s, 1 H, OH), 8.12 (d,
J = 16.6 Hz, 1 H, H-b), 7.75 (d, J = 16.6 Hz, 1 H, H-a), 7.66 (s, 4 H,
H-2¢, H-3¢, H-5¢, H-6¢), 7.58 (d, J = 8.8 Hz, 1 H, H-7), 7.07 (d,
J = 8.8 Hz, 1 H, H-6).
2-(4-Chlorophenyl)-5-methoxy-4-oxo-3,4-dihydro-2H-1-ben-
zothiopyran-8-yl 1-Piperidinecarboxylate (2e)
A suspension of 1,3-benzoxathiol-2-one 1d (X = 4-Cl; 108 mg, 0.3
mmol) in CHCl3 (4 mL) was deoxygenated with argon, and piperi-
dine (0.2 mL, 2 mmol) was added. The mixture was stirred at r.t. for
1 h and then concentrated. The residue was crystallized (CHCl3–
MeOH) to give thioflavanone 2e as a colorless solid; yield: 80 mg
(59%); mp 172–173 °C.
Anal. Calcd for C16H9BrO4S: C, 50.95; H, 2.40; S, 8.50. Found: C,
50.93, H, 2.46, S, 8.32.
5-Hydroxy-4-[(2E)-3-(4-methoxyphenyl)prop-2-enoyl]-1,3-
benzoxathiol-2-one (3c)
Substrate: 1c (X = 4-OMe); reaction time: 1 h; crystallization:
MeO(CH2)2OH; red solid; yield: 41%; mp 190–193 °C.
IR (KBr): 1717, 1678, 1420, 1217 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.51 (d, J = 8.4 Hz, 2 H, H-3¢,
H-5¢), 7.46 (d, J = 8.4 Hz, 2 H, H-2¢, H-6¢), 7.32 (d, J = 9.0 Hz, 1 H,
H-7), 6.93 (d, J = 9.0 Hz, 1 H, H-6), 4.88 (dd, J1 = 2.8 Hz, J2 = 12.3
Hz, 1 H, H-2), 3.81 (s, 3 H, OCH3), 3.52 (br s, 2 H, piperidine), 3.3–
3.4 (m, H-3, piperidine, H2O), 2.98 (dd, J1 = 2.8 Hz, J2 = 15.0 Hz, 1
H, H-3), 1.4–1.6 (m, 6 H, piperidine).
IR (KBr): 3123, 1754, 1551, 1252, 823 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.28 (br s, 1 H, OH), 8.03 (d,
J = 15.6 Hz, 1 H, H-b), 7.79 (d, J = 15.6 Hz, 1 H, H-a), 7.70 (d,
J = 8.3 Hz, 2 H, H-2¢, H-6¢), 7.59 (d, J = 8.8 Hz, 1 H, H-7), 7.18 (d,
J = 8.8 Hz, 1 H, H-6), 7.05 (d, J = 8.3 Hz, 2 H, H-3¢, H-5¢), 3.83 (s,
3 H, OCH3).
Anal. Calcd for C22H22ClNO4S: C, 61.18; H, 5.13; N, 3.24; S, 7.42.
Found: C, 61.07; H, 5.09; N, 3.37; S, 7.46.
Anal. Calcd for C17H12O5S: C, 62.19; H, 3.68; S, 9.77. Found: C,
62.08; H, 3.70; S, 9.47.
2-(4-Bromophenyl)-5-methoxy-4-oxo-3,4-dihydro-2H-1-ben-
zothiopyran-8-yl 1-Piperidinecarboxylate (2f)
A suspension of 1,3-benzoxathiol-2-one 1b (X = 4-Br; 100 mg, 0.25
mmol) in CHCl3 (5 mL) was deoxygenated with N2, and piperidine
(3 mmol, 0.3 mL) was added. The mixture was stirred at r.t. for 1 h,
and then concentrated. The residue was purified on a silica gel col-
umn (CHCl3–EtOAc, 3:1), and crystallized (MeOH) to give thiofla-
vanone 2f as a cream solid; yield: 36 mg (30%); mp 156–160 °C.
5-Hydroxy-4-[(2E)-3-(4-nitrophenyl)prop-2-enoyl]-1,3-benz-
oxathiol-2-one (3d)
Substrate: 1e (X = 4-NO2); reaction time: 1 h; crystallization:
MeO(CH2)2OH; yellow solid; yield: 68%; mp 228–232 °C.
IR (KBr): 3285, 1751, 1692, 1602, 1431, 1345 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11, 46 (br s, 1 H, OH), 8.31 (d,
J = 6.5 Hz, 2 H, H-3¢, H-5¢), 8.23 (d, J = 15.6 Hz, 1 H, H-b), 8.00
(d, J = 6.5 Hz, 2 H, H-2¢, H-6¢), 7.86 (d, J = 15.6 Hz, 1 H, H-a), 7.64
(d, J = 8.8 Hz, 1 H, H-7), 7.10 (d, J = 8.8 Hz, 1 H, H-6).
IR (KBr): 1717, 1678, 1420, 1217 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.60 (d, J = 8.3 Hz, 2 H, H-3¢,
H-5¢), 7.44 (d, J = 8.3 Hz, 2 H, H-2¢, H-6¢), 7.33 (d, J = 9.3, 1 H, H-
7), 6.93 (d, J = 9.3 Hz, 1 H, H-6), 4.87 (dd, J1 = 12.2 Hz, J2 = 2.9
Hz, 1 H, H-2), 3.81 (s, 3 H, OCH3), 3.50 (br s, 2 H, piperidine),
3.25–3.4 (m, H-3, piperidine, H2O), 2.96 (dd, J1 = 15.1 Hz, J2 = 2.9
Hz, 1 H, H-3).
Anal. Calcd for C16H9NO6S·0.5H2O: C, 54.54; H, 2.86; N, 3.97; S,
9.10. Found: C, 54.17; H, 2.93; N, 3.86; S, 9.02.
4-[(2E)-3-(3-Chlorophenyl)prop-2-enoyl]-5-hydroxy-1,3-benz-
oxathiol-2-one (3e)
Substrate: 1f (X = 3-Cl); reaction time: 2 h; crystallization: CHCl3–
MeOH; yellow solid; yield: 42%; mp 175–179 °C.
Anal. Calcd for C22H22BrNO4S: C, 55.47; H, 4.65; N, 2.94; S, 6.73.
C, 55.16; H, 4.55; N, 3.02; S, 6.72.
Cleavage of the 5-Methoxy Group in Chalcones 1: General Pro-
cedure
IR (KBr): 3319, 1749, 1631, 1596, 1430 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 11.40 (br s, 1 H, OH), 8.14 (d,
J = 15.8 Hz, 1 H, H-b), 7.81 (s, 1 H, H-2¢), 7.77 (d, J = 15.8 Hz, 1
H, H-a), 7.72 (d, J = 6.0 Hz, 1 H, H-6¢), 7.63 (d, J = 8.7 Hz, 1 H, H-
7), 7.51 (m, 2 H, H-4¢, H-5¢), 7.09 (d, J = 8.7 Hz, 1 H, H-6).
BF3·Me2S (21 mmol) was added to a soln of a 5-methoxychalcone
1 (2 mmol) in CH2Cl2 (12 mL), and the mixture was stirred at r.t.,
cooled in ice, and quenched with H2O (40 mL). The CH2Cl2 was
evaporated under vacuum, and the precipitate was filtered off, and
washed with H2O to give a crude product that was crystallized.
Anal. Calcd for C16H9ClO4S: C, 57.75; H, 2.73; S, 9.64. Found: C,
57.50; H, 2.74; S, 9.70.
Synthesis 2009, No. 11, 1811–1814 © Thieme Stuttgart · New York

1814
W. Konieczny, M. Konieczny
PAPER
7-Phenyl-7H-[1,3]oxathiolo[4,5-f][1]benzopyran-2,9(8H)-dione
(4a)
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A suspension of benzothiazolone 3a (X = H; 180 mg, 0.6 mmol) in
AcOH (2 mL) and H2SO4 (0.2 mL) was stirred at 60 °C for 4 h, then
cooled and diluted with H2O. The resulting precipitate was filtered
off, dried, and crystallized (CHCl3–MeOH) to give oxathiolofla-
vanone 4a as a colorless solid; yield: 94 mg (52%); mp 181–182 °C.
IR (KBr): 1763, 1676, 1599, 1451, 1284 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.76 (d, J = 8.8 Hz, 1 H, H-7),
7.55 (d, J = 7.3 Hz, 2 H, H-2¢, H-6¢), 7.47–7.38 (m, 3 H, H-3¢, H-4¢,
H-5¢), 7.18 (d, J = 8.8 Hz, 1 H, H-8), 5.78 (dd, J1 = 12.9 Hz, J2 = 2.4
Hz, 1 H, H-2), 3.41 (dd, J1 = 17.1 Hz, J2 = 12.9 Hz, 1 H, H-3), 2.97
(dd, J1 = 17.1 Hz, J2 = 2.4 Hz, 1 H, H-3).
Anal. Calcd for C16H10O4S: C, 64.42; H, 3.38; S, 10.75. Found: C,
64.48; H, 3.44; S, 10.52.
7-(4-Bromophenyl)-7H-[1,3]oxathiolo[4,5-f][1]benzopyran-
2,9(8H)-dione (4b)
A suspension of benzothiazolone 3b (X = 4-Br; 400 mg, 1.02 mmol)
in AcOH (1.5 mL) and H2SO4 (0.2 mL) was stirred at 80 °C for 1.5
h, then cooled and diluted with H2O. The resulting precipitate was
filtered off, dried, and crystallized [MeO(CH2)2OH] to give oxa-
thioloflavanone 4b as a beige solid; yield: 356 mg (89%); mp 229–
231 °C.
Anal. Calcd for C16H9BrO4S: C, 50.95; H, 2.40; S, 8.50. Found: C,
50.94; H, 2.43; S, 8.39.
IR (KBr): 1754, 1675, 1603, 1457, 1284 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.77 (d, J = 9.1 Hz, 1 H, H-7),
7.66 (d, J = 8.4 Hz, 2 H, H-3¢, H-5¢), 7.52 (d, J = 8.4 Hz, 2 H, H-2¢,
H-6¢), 7.20 (d, J = 9.1 Hz, 1 H, H-8), 5.80 (dd, J1 = 12.9 Hz, J2 = 3.0
Hz, 1 H, H-2), 3.38 (dd, J1 = 17.2 Hz, J2 = 12.9 Hz, 1 H, H-3), 3.00
(dd, J1 = 1 7.2 Hz, J2 = 2.9 Hz, 1 H, H-3).
(4) Rimbault, C. G. US Patent 4,885,298, 1989.
(5) Dhanak, D.; Keenan, R. M.; Burton, G.; Kaura, A.; Darcy,
M. G.; Shah, D. H.; Ridgers, L. H.; Breen, A.; Lavery, P.;
Tew, D. G.; West, A. Bioorg. Med. Chem. Lett. 1998, 8,
3677.
7-(3-Chlorophenyl)-7H-[1,3]oxathiolo[4,5-f][1]benzopyran-
2,9(8H)-dione (4c)
A suspension of benzothiazolone 3e (X = 3-Cl; 166 mg, 0.5 mmol)
in AcOH (2 mL) and H2SO4 (0.2 mL) was stirred at 80 °C for 2.5 h,
then cooled and diluted with H2O. The resulting precipitate was fil-
tered off, dried, purified on a silica gel column (CHCl3–cyclohex-
ane, 2:1), and crystallized (CHCl3–MeOH) to give
oxathioloflavanone 4c as a colorless solid; yield: 84 mg (50%); mp
155–157 °C.
(6) Wang, H.-K.; Bastow, K. F.; Cosentino, L. M.; Lee, K. H.
J. Med. Chem. 1996, 39, 1975.
(7) Dekermendjian, K.; Kahnberg, P.; Witt, M.-R.; Sterner, O.;
Nielsen, M.; Liljefors, T. J. Med. Chem. 1999, 42, 4343.
(8) Kataoka, T.; Watanabe, S.; Mori, E.; Kadomoto, R.;
Tanimura, S.; Kohno, M. Bioorg. Med. Chem. 2004, 12,
2397.
(9) Bates, D. K.; Li, K. J. Org. Chem. 2002, 67, 8662.
(10) Taylor, A. W.; Dean, D. K. Tetrahedron Lett. 1988, 29,
1845.
(11) Kataoka, T.; Watanabe, S.-i.; Mori, E.; Kadomoto, R.;
Tanimura, S.; Kohno, M. Bioorg. Med. Chem. 2004, 12,
2397.
(12) Konieczny, M. T.; Horowska, B.; Kunikowski, A.; Konopa,
J.; Wierzba, K.; Yamada, Y.; Asao, T. J. Org. Chem. 1999,
64, 359.
IR (KBr): 1753, 1680, 1602, 1457, 1287 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.80 (d, J = 8.8 Hz, 1 H, H-7),
7.68 (s, 1 H, H-2¢), 7.51, (m, 3 H, H-4¢, H-5¢, H-6¢), 7.24 (d, J = 8.8
Hz, 1 H, H-8), 5.83 (dd, J1 = 12.9 Hz, J2 = 2.0 Hz, 1 H, H-2), 3.43
(dd, J1 = 17.0 Hz, J2 = 12.9 Hz, 1 H, H-3), 3.04 (dd, J1 = 1 7.0 Hz,
J2 = 2.0 Hz, 1 H, H-3).
Anal. Calcd for C16H9ClO4S: C, 57.75; H, 2.73; S, 9.64. Found: C,
57.73; H, 2.74; S, 9.53.
(13) Konieczny, M. T.; Konieczny, W.; Sabisz, M.;
Składanowski, A.; Wakieć, R.; Augustynowicz-Kopeć, E.;
Zwolska, Z. Eur. J. Med. Chem. 2007, 42, 729.
(14) Konieczny, M. T.; Konieczny, W.; Okabe, S.; Tsujimoto, H.;
Suda, Y.; Wierzba, K. Chem. Pharm. Bull. 2006, 54, 350.
(15) Konieczny, M. T.; Konieczny, W.; Wolniewicz, S.;
Wierzba, K.; Suda, Y.; Sowiꢀski, P. Tetrahedron 2005, 61,
8648.
Acknowledgment
The authors wish to thank the Medical University of Gdaꢀsk for
grant number W-60.
Synthesis 2009, No. 11, 1811–1814 © Thieme Stuttgart · New York