Synthesis of spin labelled chromones

Article abstract of DOI:10.1055/s-2000-7115

Synthesis of spin labelled chromone 4a is described from paramagnetic acid derivatives 1a, 1b by the conventional Baker-Venkataraman procedure. Different hydroxylated paramagnetic chromone derivatives 8, 9, 12a, and 12b could be obtained by different one-pot reactions and a glycoside of 5-hydroxy-2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl) chromone radical 14b was synthesized.

Full text of DOI:10.1055/s-2000-7115

PAPER
1415
Synthesis of Spin Labelled Chromones
Éva Müller,a Tamás Kálai,a József Jekı,b Kálmán Hidega
aInstitute of Organic and Medicinal Chemistry, University of Pécs, H-7643 Pécs, P. O. Box 99, Hungary
Fax +(36)72325731; E-mail:KHIDEG@main.pote.hu
bICN Hungary Ltd., H-4440 Tiszavasvári, Pf.: 1, Hungary
Received 5 May 2000
investigate the applicability of the well established syn-
thetic procedures of flavonoid chemistry in the presence
of a stable nitroxide free radical.
Abstract: Synthesis of spin labelled chromone 4a is described from
paramagnetic acid derivatives 1a, 1b by the conventional Baker-
Venkataraman procedure. Different hydroxylated paramagnetic
chromone derivatives 8, 9, 12a, and 12b could be obtained by dif-
ferent one-pot reactions and a glycoside of 5-hydroxy-2-(1-oxyl-
2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl) chromone radical
14b was synthesized.
Compound 1c was obtained by esterification of 2-hydroxy
acetophenone with acid chloride 1a9or with mixed anhy-
dride ester 1b.10 Ester 1c could be rearranged in pyridine
with KOH to 1,3-dicarbonyl compound 2. Reaction of
compound 2 with hydrazine gave 5(3)-(2-hydroxyphe-
nyl)-3(5)-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-
pyrrol-3-yl)-pyrazole (3). Compound 2 could be cyclized
Key words: chromones, free radicals, glycosides, heterocycles, ni-
troxides
11
in acetic acid in the presence of catalytic amount H2SO4
The most widespread chromones are flavones occurring
mainly in plants. They have marked a wide range of dif-
ferent physiological effects in animals and human beings,1
although they play no part in normal metabolism. Recent-
ly, much attention has been paid to different flavonoid de-
rivatives as antioxidant compounds, and dietary intake of
these natural compounds is thought to be very important
for preventing a variety of diseases.2 The antioxidant ac-
tivity of flavones has been considered to be via two possi-
ble modes of action, radical scavenging and metal
chelating.3 The most effective compounds have an o-dihy-
droxycathecol structural element on the B ring.4 The ques-
tion of substitution of the B ring with another aromatic or
heteroaromatic ring had arisen earlier, indole,5 pyrrole,6
pyridine, and piperidine7 derivatives were synthesized.
Replacement of the carbocyclic ring B with a non-aromat-
ic paramagnetic heterocycle or its diamagnetic amine pre-
cursor compound may contribute to increase the
antioxidant effect of flavonoids.
to 2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-
3-yl)chromen-4-one (4a), which could be selectively re-
duced with acetic acid/Fe powder12 to the diamagnetic de-
rivative 4b without reduction of chromene moiety.
Compound 4a could also be achieved by another reaction
pathway: bromination of chroman-4-one 613 at a-position
to carbonyl group with pyrrolidone hydrotribromide14
(PHT) gave compound 7, which was dehydrobrominated
with DBU to 4a. Compound 6 was synthesized by acidic
cyclization from ketone 5,13 which proved to be a key
compound for synthesis of 3-hydroxy-chromen-4-one
(8)15 and 3-hydroxy-chroman-4-one (9) derivatives.
Treatment of compound 5 with basic H2O2 at 0 ∞C for 24
hours gave 2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-
1H-pyrrol-3-yl)-3-hydroxychromen-4-one (8)5 as the
main product, while treatment at room temperature for 3
hours yielded 2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-
1H-pyrrol-3-yl)-3-hydroxychroman-4-one (9) as the main
product.16 Reaction of compound 5 with hydrazine gave
4,5-dihydro-3-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-
1H-pyrrol-3-yl)-5-(2-hydroxyphenyl)-1H-pyrazole (10)
(Scheme 1, Table).
Flavonoids occur in the nature mainly as glycosides of
their polyhydroxylated derivatives,17 therefore we also at-
tempted to synthesize such paramagnetic derivatives. For-
tunately, a one-pot method described recently18 was
extendable for synthesis of 2-(1-oxyl-2,5-dihydro-
2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-hydroxychromen-
4-one (12a). Reaction of acid chloride 1a with 2,6-dihy-
droxyacetophenone in the presence of 5 equivalents of
K2CO3 in acetone gave compound 12a, and 13a biradical
as a by-product. To mimic the shape of flavone, we intro-
duced a six-membered ring instead of five-membered one.
However, the acid chloride from 11a19 proved to be unsta-
ble, therefore the imidazolide 11b, prepared by Staab’s
method,20 was used instead. In this reaction, we obtained
2-(1-oxyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethylpyridin-
Substitution of the B ring of flavonoids with a five- or six-
membered nitroxide or their amine precursor was there-
fore an attractive challenge, since these paramagnetic
moieties as well as their sterically hindered amine precur-
sors exhibit remarkable antioxidant activity by scaveng-
ing reactive oxygen intermediaries.8 The other aim was to
Synthesis 2000, No. 10, 1415–1420 ISSN 0039-7881 © Thieme Stuttgart · New York

1416
É. Müller et al.
PAPER
Reagents and conditions: a) 2-hydroxyacetophenone (1 equiv), Et3N (1.1 equiv), CH2Cl2, 0 ∞C to r.t., 1 h, (82%); b) 2-hydroxyacetophenone
.
(1 equiv), NaH (0.1 equiv), THF, 65 ∞C, 1 h, (58%); c) KOH 1.5 (equiv), pyridine, 50 ∞C, 30 min., then 10% aq HOAc, (72%); d) N2H4 H2O
(1.2 equiv), EtOH, 1 h, r.t. (40%); e) HOAc/H2SO4, 100 ∞C, 30 min., then NaHCO3, MnO2 (0.3 equiv), O2, 5 min., (25%); f) Fe (10 equiv),
HOAc, 50 ∞C, 30 min, then K2CO3, (44%); g) Ref. 13.; h) PHT (1.25 equiv), 2-pyrrolidone (1.25 equiv), THF 65 ∞C, 30 min., (68%); i) DBU
(1 equiv), CHCl3, 63 ∞C, 30 min., (72%); j) NaOH (0.4 equiv), H2O2 (4.0 equiv), 0 ∞C, 24 h, (26%); k) NaOH (0.4 equiv), H2O2 (4.0 equiv),
.
r.t. 3 h, (22%); l) N2H4 H2O (1.2 equiv), MeOH, 2 h, r.t. (60%)
Scheme 1
Mps were determined with a Boetius micro melting point apparatus
and are uncorrected. Elemental analyses (C, H, N, S) were per-
formed on Fisons EA 1110 CHNS elemental analyzer. The IR
(Specord 75) spectra were in each case consistent with the assigned
structure. Mass spectra were recorded on a VG TRIO-2 instrument
in the EI mode (70 eV, direct inlet) or with thermospray technique.
Samples were analyzed in the by-pass mode. The sample (10 mL)
solution in CH3OH was introduced via the thermospray interface.
The mobile phase was CH3OH/H2O (1:1) containing 0.1 M
NH4OAc. The capillary tip temperature was 230 ∞C, the electrode
voltage was 180 V and the source temperature was 210 ∞C. The ESR
spectra were obtained from 10-5 M solution (CHCl3), using BRUK-
ER ECS-106 spectrometer. All monoradicals exhibit three equidis-
tant lines with aN = 14.7-15.5 G. Biradical 13a exhibits quintet
lines. 1H NMR spectra were recorded with Bruker 400 spectrometer
at 400 MHz. Chemical shifts are given in ppm, relative to TMS in-
ternal standard. To obtain the high resolution NMR spectra of the
radicals, they were reduced with an excess of co-dissolved (PhNH)2
additive. Flash column chromatography was performed on Merck
Kieselgel 60 (0.040-0.063 mm). Qualitative TLC was carried out
4-yl)-5-hydroxychromen-4-one (12b) monoradical exclu-
sively, which hints that this one-pot reaction can be car-
ried out not only with acid chlorides but also with
imidazolides. Reaction of compound 12a with 2,3,4,6-tet-
ra-O-acetyl-a-D-glucopyranosyl bromide in quinoline in
the presence of Ag2O gave compound 14a in moderate
yield.21 This compound was hydrolyzed to 2-(1-oxyl-2,5-
dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-b-D-glu-
copyranosyloxychromen-4-one (14b) by Zemplen’s
method22 (Scheme 2).
In summary, spin labelled chromones and chromanes as
well as their 5- or 3-hydroxy derivatives could be synthe-
sized by application of the well-established procedures of
flavonoid chemistry. Paramagnetic pyrazole derivative
and chromone glycoside were also achieved. Investiga-
tion of biological activity of these derivatives is in
progress.
Synthesis 2000, No. 10, 1415–1420 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Spin Labelled Chromones
1417
Table Compounds 1c–14b Prepared
Product
Yield (%)
Method
Mp (∞C)
124–125
IR (Nujol) n (cm–1)
MS m/z (%)
1c
82 (A)
58 (B)
1725, 1670 (C=O) 1625, 1590 (C=C)
302 (M+, 8), 288 (6), 137 (45), 109 (100)
302 (M+, 7), 288 (16), 257 (15), 121 (100)
2
72
40
110–111
228–230
131–132
1615 (C=O) 1570 (C=C)
3
3200 (NH) 1610, 1580, 1540, 1505 (C=C)
1630 (C=O) 1610, 1560 (C=C)
298 (M+, 31), 284 (67), 268 (95), 253 (100)
284 (M+, 27), 270 (45), 254 (53), 121 (100)
4a
25 (A)
72 (B)
4b
7
44
68
90– 91
3300 (NH), 1630 (C=O) 605, 1555 (C=C)
1675 (C=O) 1600, 1575 (C=C)
269 (M+, <1), 254 (100), 239 (8), 134 (13)
140–141
364/366 (M+, 11/11), 350/352 (11/11), 147
(40), 121 (100)
8
26
22
60
78
15
17
8
166–167
93– 95
3240 (OH), 1620 (C=O) 1605, 1555 (C=C)
1710 (C=O) 1630, 1600 (C=C)
3260 (NH) 1610, 1590, 1560 (C=C)
1690 (C=O) 1590 (C=C)
300 (M+, 3), 270 (17), 154 (93), 41 (100)
302 (M+, 3), 196 (33), 135 (39), 41 (100)
300 (M+, 3), 286 (8), 270 (10), 161 (100)
248 (M+, <1), 184 (10), 168 (35), 68 (100)
300 (M+, 40), 286 (67), 270 (61), 137 (100)
314 (M+, 31), 300 (100), 284 (69), 269 (35)
TSP: 467 (M+H)+
9
10
160–161
42– 44
11b
12a
12b
13
148–149
184–185
208–209
72– 74
1650 (C=O) 1610, 1555 (C=C
1645 (C=O) 1600 (C=C)
1650, 1640 (C=O) 1595 (C=C)
1740, 1640 (C=O) 1600 (C=C)
3320 (OH), 1630 (C=O) 1600 (C=C)
14a
14b
36
41
TSP: 631 (M+H)+
125–126
TSP: 463 (M+H)+
on commercially prepared plates (20 ¥ 20 ¥ 0.02 cm) coated with
Merck Kieselgel GF254. Compounds 1a,9 1b,10 5,13 6,13 11a19 were
prepared according to published procedures. The physical and spec-
tral data of all new compounds are listed in the Table.
1-(1-Oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-3-
(2¢-hydroxyphenyl)-propane-1,3-dione Radical (2)
To a stirred solution of compound 1c (1.51 g, 5 mmol) in pyridine
(10 mL) was added KOH (421 mg, 7.5 mmol) at 50 ∞C, then the
mixture was stirred further for 30 min. The mixture was poured onto
crushed ice (30 g) and 10% aqueous HOAc (10 mL) was added,
upon which compound 2 crystallized out. After filtration, com-
pound 2 was obtained as a yellow solid (1.10 g, 72%); mp: 110-111∞C;
Rf 0.50 (hexane/EtOAc, 2:1).
3-(2¢-Acetyl-carboxyphenyl)-2,2,5,5-tetramethyl-2,5-dihydro-
1H-pyrrol-1-yloxyl Radical (1c)
Method A
To a stirred solution of 2-hydroxyacetophenone (1.36 g, 10.0 mmol)
and Et3N (1.11 g, 11.0 mmol) in CH2Cl2 (20 mL) was added com-
pound 1a (2.02 g, 10.0 mmol) in CH2Cl2 (10 mL) dropwise at 0 ∞C,
then the mixture was stirred further for 1 h at r.t. The organic phase
was washed with brine (10 mL), separated, dried (MgSO4), filtered,
and evaporated. The residue was crystallized from hexane to give
compound 1c as a pale yellow solid (2.47 g, 82%); mp: 124-125
∞C; Rf 0.36 (hexane/EtOAc, 2:1).
5(3)-(2-Hydroxyphenyl)-3(5)-(1-oxyl-2,5-dihydro-2,2,5,5-tet-
ramethyl-1H-pyrrol-3-yl)-pyrazole Radical (3)
To a solution of compound 2 (302 mg, 1 mmol) in EtOH (10 mL)
was added hydrazine monohydrate (60 mg, 1.2 mmol) and the mix-
ture was allowed to stand at r.t. After 1 h, brine was added (5 mL),
and then extracted with CHCl3 (2 ¥ 10 mL). The organic phase was
separated, dried (MgSO4), and filtered. The residue was purified by
flash column chromatography (hexane/Et2O), to yield compound 3
as a pale yellow solid (119 mg, 40%); mp: 228-230 ∞C; Rf 0.30
(hexane/EtOAc, 2:1).
Method B
To a stirred solution of 2-hydroxyacetophenone (1.36 g, 10.0 mmol)
and compound 1b (2.56 g, 10.0 mmol) in anhyd THF (30 mL) was
added NaH (24 mg, 1.0 mmol) and the mixture was further stirred
under reflux for 1 h. After cooling, EtOH (0.5 mL) and then Et2O
(20 mL) were added. The organic phase was washed with brine
(20 mL), separated, dried (MgSO4), filtered, and evaporated. The
residue was purified by flash column chromatography (hexane/
Et2O) to give the title compound 1c (1.75 g, 58%).
2-(1-Oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-
chromen-4-one Radical (4a)
Method A
To a stirred solution of compound 2 (906 mg, 3.0 mmol) in HOAc
(10 mL) was added 98% H2SO4 (0.15 mL). The mixture was heated
at 100 ∞C for 30 min, then poured onto crushed ice (50 g). The so-
lution was made basic by addition of NaHCO3, and extracted with
CHCl3 (3 ¥ 20 mL). The organic phase was separated and dried
Synthesis 2000, No. 10, 1415–1420 ISSN 0039-7881 © Thieme Stuttgart · New York

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É. Müller et al.
PAPER
Reagents and conditions: a)1,1¢-carbonyldiimidazole (1.1 equiv), THF, 65 ∞C, 20 min., (78%); b) 2,6-dihydroxyacetophenone (1 equiv), K2CO3
(5 equiv), acetone, 56 ∞C, 24 h, then 1 M aq HCl, MnO2 (0.1-0.2 equiv), O2, 5 min., (8-17%); c) 12a, 2,3,4,6-tetra-O-acetyl-a-D-glucopyra-
nosylbromide (1 equiv), Ag2O (1 equiv), quinoline, 70 ∞C, 4 h, (36%); d) NaOMe (0.6 equiv), MeOH, 1 h, r.t., then aq NH4Cl, (41%).
Scheme 2
(MgSO4). Activated MnO2 (100 mg, 1.15 mmol) was added, O2 was
bubbled through for 5 min., the mixture was filtered, and evaporat-
ed. After purification of the residue, compound 4a was obtained as
a yellow solid (220 mg, 25%); mp: 131-132 ∞C; Rf 0.27 (hexane/
EtOAc, 2:1).
3-Bromo-2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-
3-yl)chroman-4-one Radical (7)
To a stirred solution of compound 6 (572 mg, 2.0 mmol) in dry THF
(20 mL) were added 2-pyrrolidinone (215 mg, 2.5 mmol) and PHT
(1.24 g, 2.5 mmol), and the mixture was refluxed for 30 min. The
cooled mixture was filtered, the organic phase was washed with
H2O (20 mL), dried (MgSO4), and evaporated to dryness. The resi-
due was purified by flash column chromatography (hexane/Et2O),
to give the title compound 7 as a pale yellow solid (500 mg, 68%);
mp: 140-141∞C; Rf 0.48 (hexane/EtOAc, 2:1).
Method B
To a stirred solution of 7 (730 mg, 2.0 mmol) in dry CHCl3 (20 mL)
was added DBU (304 mg, 2.0 mmol), and the mixture was refluxed
for 30 min. The cooled mixture was washed with 5% H2SO4
(20 mL) then with H2O (20 mL), separated, dried (MgSO4), and
evaporated. The crude material was purified by flash column chro-
matography (hexane/Et2O) to give compound 4a (409 mg, 72%).
3-Hydroxy-2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyr-
rol-3-yl)chromen-4-one Radical (8)
To a stirred solution of compound 5 (1.43 g, 5.0 mmol) in MeOH
(10 mL) were added 8% NaOH (1 mL) and 30% aqueous H2O2
(2.4 mL) at 0 ∞C, then the mixture was allowed to stand at 0 ∞C for
24 h. The MeOH was evaporated in vacuo at 30 ∞C, and the solution
was acidified with 1 M HCl, upon which a gummy solid precipitat-
ed. The solid was filtered off and further purified by flash column
chromatography (hexane/Et2O) to afford compound 8 (400 mg,
26%), as a yellow solid; mp: 166-167 ∞C; Rf 0.40 (hexane/EtOAc,
2:1).
2-(2,5-Dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)chromen-4-
one (4b)
To a stirred solution of 4a (284 mg, 1.0 mmol) in HOAc (5 mL) was
added Fe powder (560 mg, 10.0 mmol) and the mixture was warmed
gently to 50 ∞C and kept at this temperature for 30 min. The mixture
was diluted with H2O (20 mL), and the solution was decanted from
Fe powder. The mixture was basified with K2CO3 to pH 8, and ex-
tracted with CHCl3 (3 ¥ 20 mL). The combined organic phases were
dried (MgSO4), filtered, and evaporated. The residue was purified
by flash column chromatography (CHCl3/Et2O) to give compound
4b as a white solid (120 mg, 44%); mp: 90-91 ∞C; Rf 0.33 (CHCl3/
MeOH, 9:1).
3-Hydroxy-2-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyr-
rol-3-yl)chroman-4-on Radical (9)
To a stirred solution of compound 5 (286 mg, 1.0 mmol) in MeOH
(5 mL) were added 8% NaOH (0.2 mL) and 30% aqueous H2O2
(0.5 mL), then the mixture was stirred at r.t. for 3 h. The MeOH was
evaporated in vacuo at 30 ∞C, the solution was diluted with H2O
(10 mL), acidified with 1 M HCl, and extracted with CHCl3
(2 ¥ 20 mL). The organic phase was separated, dried (MgSO4),
1H NMR (400 MHz, CDCl3): d = 1.34 (s, 6H), 1.52 (s, 6H), 6.44 (s,
1H), 6.56 (s, 1H), 7.34-7.44 (m, 2H), 7.62-7.68 (m, 1H), 8.14-
8.18 (dd, 1H).
Synthesis 2000, No. 10, 1415–1420 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Spin Labelled Chromones
1419
filtered, and evaporated. The residue was purified by flash column
chromatography (hexane/EtOAc) then (CHCl3/Et2O) to yield com-
pound 9 (68 mg, 22%), as a yellow solid; mp: 93-95 ∞C; Rf 0.59
(CHCl3/MeOH, 4:1).
2-(1-Oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-
(b-D-2,3,4,6-tetra-O-acetyl-glucopyranosyloxy)chromen-4-one
Radical (14a)
A mixture of compound 12a (300 mg, 1.0 mmol) and 2,3,4,6-tetra-
O-acetyl-a-D-glucopyranosyl-bromide (411 mg, 1.0 mmol) and
Ag2O (232 mg, 1.0 mmol) in quinoline (8 mL) was stirred at 70 ∞C
for 4 h. The mixture was then poured onto a mixture of crushed ice
(40 g) and 2 M HCl (40 mL). The solution was extracted with
EtOAc (2 ¥ 30 mL), the organic phase was dried (MgSO4), filtered,
and evaporated. The residue was purified by flash column chroma-
tography (hexane/EtOAc) then (CHCl3/Et2O) to give compound
14a (230 mg, 36%) as a brownish-yellow solid; mp: 72-74 ∞C; Rf
0.66 (CHCl3/MeOH, 9:1).
4,5-Dihydro-3-(1-oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyr-
rol-3-yl)-5-(2-hydroxyphenyl)-1H-pyrazole Radical (10)
To a solution of compound 5 (286 mg, 1.0 mmol) in MeOH (5 mL)
and H2O (5 mL) was added hydrazine monohydrate (60 mg,
1.2 mmol), and the mixture was allowed to stand at r.t. for 2 h. Com-
pound 10 (80 mg, 60%) crystallized out spontaneously as yellow
pellets; mp: 160-161 ∞C; Rf 0.33 (hexane/EtOAc, 2:1).
1H NMR (400 MHz, DMSO-d6): d = 1.10 (s, 3H), 1.12 (s, 3H), 1.18
(s, 3H), 1.19 (s, 3H) 2.79 (q, 1H), 3.45 (q, 1H), 4.22 (dt, 1H, J = 4
Hz), 5.61 (s, 1H).
2-(1-Oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-
(b-D-glucopyranosyloxy) chromen-4-one Radical (14b)
To a solution of compound 14a (200 mg, 0.31 mmol) in dry MeOH
(10 mL) was added freshly-made NaOMe solution [1 mL, Na
(100 mg) dissolved in dry MeOH (10 mL)], and the mixture was al-
lowed to stand for 1 h at r.t. The solvent was evaporated off, and the
residue was dissolved in sat. NH4Cl (10 mL). The mixture was
evaporated to dryness, the residue was redissolved in MeOH/CHCl3
(1:1, 40 mL), filtered, and evaporated. The residue was purified by
flash column chromatography (CHCl3/MeOH) to give the title com-
pound 14b as a yellow solid 60 mg (41%); mp: 125-126 ∞C; Rf 0.51
(CHCl3/MeOH, 4:1).
N-(1-oxyl-1,2,5,6-tetrahydro-2,2,6,6-tetramethylpyridin-4-car-
boxylic Acid)imidazole Radical (11b)
A solution of acid 11a (990 mg, 5.0 mmol) and 1,1¢ -carbonyldiim-
idazole (891 mg, 5.5 mmol) in anhyd THF (15 mL) was refluxed for
20 min. After cooling, Et2O (15 mL) was added, and the solution
washed with cold sat. NaHCO3 (15 mL). The organic phase was
separated, dried (MgSO4), filtered, and evaporated. The residue was
crystallized from hexane/Et2O to give compound 11b (970 mg,
78%) as an orange solid; mp: 42-44 ∞C; Rf 0.36 (CHCl3/MeOH,
9:1).
2-(1-Oxyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-
hydroxychromen-4-one Radical (12a) and 2-(1-Oxyl-2,5-dihy-
dro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)-5-[(1-oxyl-2,5-dihy-
dro-2,2,5,5-tetramethyl-1H-pyrrol-3-yl)carbonyloxy]chromen-
4-one Biradical (13)
Acknowledgement
This work was supported by grants from the Hungarian National
Research Foundation (OTKA T030013) and Hungarian Ministry of
Education (FKFP 0252/1999). The authors wish to express their
thanks to Dr. Z. Berente (Inst. of Biochemistry, Univ. of Pécs) for
NMR measurements, M. Balog for technical assistance and M.
Szabó (ICN Hungary Ltd.) for mass spectral measurements.
To a stirred mixture of compound 2,6-dihydroxyacetophenone
(1.52 g, 10.0 mmol) and K2CO3 (6.90 g, 50.0 mmol) in dry acetone
(40 mL) was added 1a (2.02 g, 10.0 mmol) dissolved in dry acetone
(10 mL) dropwise during 5 min., and the mixture was stirred under
reflux for 24 h. After cooling, acetone was evaporated off, the resi-
due was dissolved in H2O (10 mL), acidified with 1 M HCl, and ex-
tracted with CHCl3 (2 ¥ 30 mL). The organic phase was separated
and dried (MgSO4). Activated MnO2 (100 mg, 1.15 mmol) was add-
ed, O2 was bubbled through for 5 min., the mixture was then fil-
tered, and evaporated. After chromatography (hexane/Et2O
followed by hexane/EtOAc), compound 12a (450 mg, 15%) was
obtained from the first band at Rf 0.46 (hexane/EtOAc, 2:1); mp:
148-149 ∞C. The second band at Rf 0.33 (hexane/EtOAc, 2:1) gave
13 (400 mg, 8%); mp: 208-209 ∞C.
References
(1) Middleton, E.; Kandaswami, C. In The Flavonoids; Harborne,
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5-hydroxychromen-4-one (12b)
A mixture of compound 2,6-dihydroxyacetophenone (760 mg,
5.0 mmol) and K2CO3 (138 mg, 1.0 mmol) was stirred for 10 min.,
then compound 11b (1.24 g, 5.0 mmol) in dry acetone (10 mL) was
added dropwise. The mixture was stirred for 1 h, further K2CO3
(3.31 g, 24.0 mmol) was added and the mixture was stirred under re-
flux for 24 h. After cooling, acetone was evaporated off, the residue
was dissolved in H2O (10 mL), acidified with 1 M HCl, and extract-
ed with CHCl3 (2 ¥ 30 mL). The organic phase was separated and
dried (MgSO4). Activated MnO2 (100 mg, 1.15 mmol) was added,
O2 was bubbled through for 5 min., the mixture was filtered, and
evaporated. After chromatography (hexane/Et2O), compound 12b
(280 mg, 17%) was obtained as an orange solid; mp: 184-185 ∞C;
Rf 0.53 (hexane/EtOAc, 2:1).
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