A mild and efficient protocol for the protection of 3-hydroxychromones under phase-transfer catalysis

Article abstract of DOI:10.1055/s-0030-1260034

A mild and efficient protocol for the introduction of different protecting groups on 3-hydroxychromones (3-HCs) under phase-transfer catalysis conditions in toluene or dichloromethane/aqueous potassium hydroxide system in the presence of crown ether has been developed. The method is useful for the protection of base-sensitive chromone derivatives. Protected chromones are easier to handle and to purify, and therefore suitable for further chemical transformations. The protecting groups were cleaved cleanly using standard conditions. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260034

PAPER
2159
A Mild and Efficient Protocol for the Protection of 3-Hydroxychromones
Under Phase-Transfer Catalysis
H
ydroxy Group Pr
m
otection in 3-Hydro
y
xychromone
t
s
ro Dziuba, Rachid Benhida, Alain Burger*
Laboratoire de Chimie des Molécules Bioactives et des Arômes, UMR 6001 CNRS, Institut de Chimie de Nice,
Université de Nice-Sophia Antipolis, 28 avenue de Valrose, 06108 Nice Cedex 2, France
Fax +33(4)92076151; E-mail: burger@unice.fr
Received 7 March 2011; revised 6 April 2011
ties. In the literature, the most common approach for pro-
tection is based on acylation of the hydroxy group of 3-
HC. Treatment of 3-HCs with anhydrides or acid chlo-
rides in basic media (pyridine, NaOH, or Et3N) takes sig-
Abstract: A mild and efficient protocol for the introduction of dif-
ferent protecting groups on 3-hydroxychromones (3-HCs) under
phase-transfer catalysis conditions in toluene or dichloromethane/
aqueous potassium hydroxide system in the presence of crown ether
has been developed. The method is useful for the protection of base- nificant time,2f and often gives unsatisfactory yields.3 In
sensitive chromone derivatives. Protected chromones are easier to
addition, none of these protocols are of broad applicabili-
handle and to purify, and therefore suitable for further chemical
ty. Furthermore, in a program aimed to label oligonucle-
transformations. The protecting groups were cleaved cleanly using
otides (ODNs) with 3-HC-containing fluorescent
standard conditions.
nucleosides,4 we had to face the problem of compatibility
Key words: 3-hydroxychromone, phase-transfer catalysis, protect-
ing groups, acylation, alkylation, cleavage
of the hydroxy protecting group for 2-bromo-3-hydroxy-
chromone (Figure 1, R = Br) amenable to transformation
into the target nucleoside analogue4 and incorporation in
ODNs.5 Treatment of 2-bromo-3-HC with acylating re-
3-Hydroxychromones (Figures 1, 3-HCs) are oxygen-
agent (CbzCl) in polar aprotic solvents such as pyridine or
containing heterocyclic compounds mainly found in natu-
DMF in the presence of trialkylamines or potassium car-
ral products. This important family of compounds has at-
bonate gave poor results due to the slow conversion rate
tractive properties for different applications. For instance,
and to the instability of the starting compound in such ba-
molecules containing the 3-HC core display a wide range
sic media. Silyl-based protecting groups (TBDMS, SEM)
of biological activities.1 In addition, 2-aryl-3-HCs demon-
were unstable while the MEM was found too resistant and
strate striking fluorescent properties. 3-HCs are multi-
problematic during acidic treatment of labeled ODNs due
parametric photophysical probes that are highly sensitive
to strand cleavage. Altogether, these examples show that
to the environmental change. These unique properties
a mild and general protocol for introducing hydroxy pro-
have been applied for probing lipid bilayers, cell mem-
tecting groups on 3-HCs compatible with chemical ma-
branes, proteins and nucleic acids, and in fluorescence cell
nipulation and transformation would be of great interest
for this important family of compounds. Herein, we de-
imaging in microbiology.2
scribe an easy protocol for the hydroxy protection of dif-
O
ferent 3-HCs, including the base sensitive 2-bromo-3-HC,
using phase-transfer catalysis6 and various acylating and
OH
3-HC
alkylating reagents. The conditions to cleave the protect-
O
R
ing groups and an example illustrating the usefulness of
protected 2-bromo-3-HC in the preparation of the fluores-
cent 3-hydroxy-2-thienyl-chromone are also given.
Figure 1 3-Hydroxychromone core structure
The development of new 3-HCs is hampered by the fact The investigation was started with the unsubstituted 3-HC
that synthetic manipulations are made complex by several (1a) and benzyl chloroformate as a model reaction in dif-
factors. The solubility of many 3-HCs is low in commonly ferent phase-transfer catalysis (PTC) conditions
used organic solvents. Together, the carbonyl and hy- (Table 1).
droxy groups make 3-HC a good bidentate ligand able to
The different conditions tested were selected from litera-
coordinate metal ions and make chromatography purifica-
ture reports on phenols with acylating or alkylating re-
tion more difficult likely due to metallic species contami-
agents.7 One classical approach consists in reacting
nating silica gel. Therefore, manipulation of 3-HCs
phenols with acyl or alkyl halides using quaternary amine
requires the utilization of acceptable protecting groups,
salts such as benzyltriethylammonium chloride (TEBAC)
not only to mask the intrinsic reactivity of the hydroxy
as phase-transfer catalyst.7b Using a mixture of 3-HC (1a)
in toluene/aqueous sodium hydroxide with 1.5 equiva-
group, but also to improve their chemicophysical proper-
lents of benzyl chloroformate and a catalytic amount of
TEBAC furnished the corresponding carbonate product
2a in a modest 40% isolated yield after 30 minutes, al-
SYNTHESIS 2011, No. 13, pp 2159–2164
Advanced online publication: 06.05.2011
DOI: 10.1055/s-0030-1260034; Art ID: Z25511SS
x
x.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

2160
D. Dziuba et al.
PAPER
In several cases (Table 2, entries 10, 11, 12, and 15) tolu-
ene–dichloromethane mixture or dichloromethane were
used as the organic phase instead of toluene to improve
the solubility of the final product. We observed that the
conversion rate depends on the organic halide used. Fast
couplings were observed with chloroformates (entries 1–
9), while the reaction with benzoyl chloride (entries 10–
12) and benzyl bromide (entries 13–15) required pro-
longed reaction times, couplings with the latter displaying
the slowest rates. In all cases, good to excellent yields of
protected chromones were obtained with only 1.5 equiva-
lents of halide reagent except for 2m and 2o where 3
equivalents were employed. Thus, the PTC conditions de-
scribed herein allow the introduction of different orthogo-
nal protecting groups on the 3-HCs tested including the
base sensitive bromo derivative 1c (entries 3, 6, 9, 12, and
15). Furthermore, the protecting groups were cleaved
cleanly using standard conditions: the benzyl carbonate
and benzyl groups of 2b and 2n with hydrogen and cata-
lytic Pd/C (10%), the Alloc protecting group of 2e with di-
ethylamine and catalytic Pd(PPh3)4, and the ethyl
carbonate and benzoate groups of 2h and 2k with ammo-
nium hydroxide in ethanol–water.8
Table 1 Survey of the Reaction Conditions with CbzCl
O
O
O
O
O
O
OH
CbzCl
O
1a
2a
Entry Solvent, basea
Catalystb
Time
(min)
Yield
(%)c
1
2
3
4
5
6
toluene, NaOH
CH2Cl2, NaOH
CH2Cl2, KOH
toluene, KOH
toluene, KOH
toluene, KOH
TEBACd
30 min
30 min
10 min
10 min
30 min
>24 h
40
89
95
97
96
TEBAC
18-crown-6
18-crown-6
Kryptofix222e
tris-DHA
f
–
a The bases were used as 25% solution in H2O.
b Catalyst (5 mol%).
c Isolated yield.
d Benzyltriethylammonium chloride.
e Potassium binding cryptand.
f No conversion.
These conditions were also applied for several other com-
pounds. For example, compound 2p was described as a
blood fat decreasing agent and was synthesized previous-
ly in 47% yield.3a When the flavone 1d was reacted under
the aforementioned PTC conditions with 4-methoxyben-
zoyl chloride, compound 2p was obtained now in near
quantitative yield (Scheme 1).
though the conversion was not completed (Table 1, entry
1). In contrast, when toluene was changed to dichlo-
romethane, the conversion rate was improved and the
product 2a was obtained in 89% yield (entry 2). More-
over, when the reaction was conducted in either dichlo-
romethane or toluene and aqueous potassium hydroxide
with 18-crown-6 as the potassium-transfer catalyst,7b we
found that it gave the best results for 3-HC protection (95
and 97%, 10 min conversion, entries 3 and 4). Proceeding
under the same reaction conditions, but in the presence of
Kryptofix 222 as the catalyst,7c did not give any more ad-
vantage (entry 5). Using tris-dioxaheptylamine as the
phase-transfer catalyst7b no conversion of the starting ma-
terial was observed even with excess of acylating reagent
and prolonged reaction time (3 equiv, >24 h, entry 6).
The protected bromo derivative proved to be a suitable in-
termediate to introduce molecular diversity at position 2.
For example, the benzyloxycarbonate protected com-
pound 2c is a convenient building block in Pd(0)-cata-
lyzed carbon–carbon bond formation using Stille
coupling conditions (Scheme 2).
O
O
OCbz
Br
OR
i
In the second step of this investigation, the scope of the
optimized conditions set up for the model compound for
the preparation of three series of 3-hydroxychromones
protected with different acylating and alkylating groups
was extended.8 The results are presented in Table 2.
S
O
O
2c
3 R = Cbz
4 R = H
ii
Scheme 2 Coupling reaction with protected HC. Reagents and con-
ditions: i: 2-tributylstannylthiophene, Pd(PPh3)4, CuI, toluene, reflux,
1 h, 95%; ii) NH4OH, EtOH–H2O, r.t., 3 h, 97%.
Typical experiments were conducted with 5 mol% of
crown ether, 3-HC (1–10 mmol scale) and organic halide
in a mixture of toluene and aqueous potassium hydroxide.
OMe
O
O
O
OH
O
4-MeOC6H4COCl
OMe
OMe
OMe
OMe
CH2Cl2, aq KOH
18-crown-6
97%
O
O
1d
2p
Scheme 1 Application of the PTC conditions to the preparation of the methoxybenzoyl ester 2p
Synthesis 2011, No. 13, 2159–2164 © Thieme Stuttgart · New York

PAPER
Hydroxy Group Protection in 3-Hydroxychromones
2161
Table 2 Reaction Conditions for the Synthesis of Protected Chromones 2a–o
O
O
OH
R
O
R
aq KOH, 18-crown-6
reagent, solvent
PG
O
O
1a R = H
1b R = Ph
1c R = Br
2a–o
Entry
Reagenta
Solvent
toluene
Product
Time (min) Yield (%)b
O
O
1
2
BnOCOCl
2a
2b
2c
2d
2e
2f
10
10
20
5
97
95
88
93
98
75
90
99
91
76
96
73
Cbz
Cbz
Cbz
Alloc
Alloc
O
O
O
BnOCOCl
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
O
O
Ph
O
3
BnOCOCl
O
O
Br
O
4
H2C=CHCH2OCOCl
H2C=CHCH2OCOCl
H2C=CHCH2OCOCl
EtOCOCl
O
O
O
5
5
O
O
Ph
O
Br
O
6
20
5
Alloc
CO2Et
CO2Et
CO2Et
Bz
O
O
7
2g
2h
2i
O
O
O
8
EtOCOCl
5
O
O
Ph
O
9
EtOCOCl
20
240
5
O
O
Br
c
O
10
11
12
PhCOCl
toluene–CH2Cl2
toluene–CH2Cl2
toluene–CH2Cl2
2j
O
O
O
PhCOCl
2k
2l
Bz
O
O
Ph
O
PhCOCl
90
Bz
O
Br
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2162
D. Dziuba et al.
PAPER
Table 2 Reaction Conditions for the Synthesis of Protected Chromones 2a–o (continued)
O
O
O
OH
R
O
R
aq KOH, 18-crown-6
reagent, solvent
PG
O
1a R = H
1b R = Ph
1c R = Br
2a–o
Entry
Reagenta
BnBrd
Solvent
toluene
Product
Time (min) Yield (%)b
O
O
13
14
15
2m
2n
2o
480
360
360
71
92
94
Bn
Bn
Bn
O
O
O
BnBr
toluene
CH2Cl2
O
O
Ph
O
BnBrd
O
Br
a Reaction conditions: reagent (1.5 equiv) and 18-crown-6 (5 mol%).
b Yield of pure isolated product.
c Ratio = 1:1 (v/v).
d BnBr (3 equiv) and 18-crown-6 (10 mol%) were used in this case to accelerate the reaction (see text).
Thus, the reaction of 2c with 2-tributylstannylthiophene in In summary, a convenient phase-transfer catalysis proto-
the presence of catalytic Pd(PPh3)4 in refluxing toluene af- col for the introduction of different protecting groups on
forded the coupling product 3 in 95% yield. Removal of 3-HCs has been developed. The protected chromones are
the protecting group by treatment with ammonia in aque- easier to handle and to purify and therefore suitable for
ous ethanol solution gave quantitatively the fluorescent- further chemical transformations. Removal of the protect-
ing compound, 3-hydroxy-2-thienylchromone (4). The ed groups was achieved conveniently using standard con-
fluorescence spectra of 4 is displayed in Figure 2.9 It ditions.
should be mentioned that this approach complements the
main methods of obtaining 3-hydroxychromones.10
Standard column chromatography was performed on 230–400 mesh
silica gel using flash column chromatography techniques.11 Analyt-
ical TLC was performed on Merck precoated silica gel 60 F254
plates. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruk-
er Avance Spectrometer 200 (200 MHz for 1H and 50 MHz for 13C).
Chemical shifts are reported in ppm relative to residual CHCl3 sig-
1
nal as an internal reference (7.26 ppm for H and 77.16 for 13C).
Spin-spin coupling constants are reported in hertz (Hz). High-reso-
lution mass spectra (HRMS) were recorded on Hybride LTQ Orbi-
trap (Thermoscientific) apparatus. Compounds 1a, 1c, and 1d were
synthesized according to known procedures.4,6c
Protection of 3-HCs with Organic Halides; General Procedure
A stirring bar and 3-HC 1 (1 mmol) were placed in a 15 mm dia-
meter test tube. Then, solvent (toluene or CH2Cl2, 4 mL), organic
halide (1.5 to 3 mmol), and 18-crown-6 (5–10% mol) were added.
After that, aq KOH (25%, 1 mL) was added at once and the mixture
was kept under intense stirring at r.t. In the binary system used, the
conversion of the 3-HC was easily monitored. Indeed, the unpro-
tected 3-HC was poorly soluble in either the organic and aqueous
phases while the product was only soluble in the organic phase.
Thus the disappearance of the precipitate in the reaction vessel in-
Figure 2 Normalized fluorescence spectra: (1) protected 3 in
MeOH (exc. = 330 nm), (2) deprotected 4 in CH2Cl2 (exc. = 360 nm).
In CH2Cl2, 3-HC 4 exhibits two emission bands: the low emissive
dicated complete conversion of the starting material as further evi-
denced by TLC (cyclohexane–EtOAc, 7:3). After completion of the
reaction, the organic layer was separated and the aqueous phase was
extracted with CH2Cl2 (2 × 5 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuum. The
normal band centered at 417 nm and the highly emissive and red shif-
ted tautomer band centered at 542 nm resulting from excited state in-
tramolecular proton transfer (ESIPT).2b,4
Synthesis 2011, No. 13, 2159–2164 © Thieme Stuttgart · New York

PAPER
Hydroxy Group Protection in 3-Hydroxychromones
2163
crude product was purified by silica gel flash chromatography with
cyclohexane–EtOAc (Table 2).
HRMS: m/z [M + H]+ calcd for C13H10BrO5: 324.9706; found:
324.9710.
Benzyl 4-Oxo-4H-chromen-3-yl Carbonate (2a)
Yield: 288 mg (97%); Rf = 0.40 (cyclohexane–EtOAc, 7:3).
Ethyl 4-Oxo-4H-chromen-3-yl Carbonate (2g)
Yield: 211 mg (90%); Rf = 0.34 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.28 (dd, J = 8.1, 1.5 Hz, 1 H), 8.09 (s, 1 H), 7.71 (m,
1H NMR: d = 8.24 (dd, J = 8.0, 1.7 Hz, 1 H), 8.08 (s, 1 H), 7.80–
7.58 (m, 1 H), 7.55–7.31 (m, 2 H), 4.33 (q, J = 7.1 Hz, 2 H), 1.38 (t,
J = 7.1 Hz, 3 H).
13C NMR: d = 171.74, 156.09, 152.64, 148.38, 137.59, 134.13,
126.21, 125.48, 124.51, 118.38, 65.75, 14.17.
1 H), 7.35–7.59 (m, 7 H), 5.31 (s, 2 H).
13C NMR: d = 171.72, 156.15, 152.74, 148.44, 137.65, 134.52,
134.22, 128.95, 128.81, 128.65, 126.32, 125.58, 124.58, 118.44,
71.24.
HRMS: m/z [M + H]+ calcd for C17H13O5: 297.0758; found:
HRMS: m/z [M + H]+ calcd for C12H11O5: 235.0601; found:
297.0762.
235.0602.
Benzyl 4-Oxo-2-phenyl-4H-chromen-3-yl Carbonate (2b)
Yield: 354 mg (95%); Rf = 0.39 (cyclohexane–EtOAc, 7:3).
Ethyl 4-Oxo-2-phenyl-4H-chromen-3-yl Carbonate (2h)
Yield: 309 mg (99%); Rf = 0.38 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.29 (dd, J = 8.0, 1.6 Hz, 1 H), 7.97–7.82 (m, 2 H),
1H NMR: d = 8.27 (dd, J = 8.0, 1.6 Hz, 1 H), 8.03–7.83 (m, 2 H),
7.82–7.64 (m, 1 H), 7.63–7.36 (m, 5 H), 4.32 (q, J = 7.1 Hz, 2 H),
1.36 (t, J = 7.1 Hz, 3 H).
13C NMR: d = 172.39, 156.33, 155.69, 152.39, 134.18, 134.10,
131.51, 129.83, 128.87, 128.56, 126.19, 125.37, 123.77, 118.24,
65.71, 14.21.
7.79–7.66 (m, 1 H), 7.61–7.32 (m, 10 H), 5.29 (s, 2 H).
13C NMR: d = 172.27, 156.38, 155.61, 152.46, 134.68, 134.18,
134.01, 131.51, 129.64, 128.82, 128.69, 128.49, 128.27, 126.13,
125.39, 123.72, 118.22, 70.99.
HRMS: m/z [M + H]+ calcd for C23H17O5: 373.1071; found:
373.1075.
HRMS: m/z [M + H]+ calcd for C18H15O5: 311.0914; found:
311.0915.
Benzyl 2-Bromo-4-oxo-4H-chromen-3-yl Carbonate (2c)
Yield: 331 mg (88%); Rf = 0.44 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.24 (dd, J = 8.2, 1.5 Hz, 1 H), 7.82–7.65 (m, 1 H),
7.57–7.34 (m, 7 H), 5.34 (s, 2 H).
13C NMR: d = 170.08, 156.45, 151.76, 142.69, 136.37, 134.50,
134.38, 128.89, 128.76, 128.40, 126.53, 126.22, 123.51, 117.89,
71.39.
HRMS: m/z [M + H]+ calcd for C17H12BrO5: 374.9863; found:
374.9868.
Ethyl 2-Bromo-4-oxo-4H-chromen-3-yl Carbonate (2i)
Yield: 284 mg (91%); Rf = 0.45 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.23 (dd, J = 8.0, 1.4 Hz, 1 H), 7.81–7.65 (m, 1 H),
7.59–7.39 (m, 2 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.42 (t, J = 7.1 Hz, 3
H).
13C NMR: d = 170.01, 156.29, 151.52, 142.51, 136.20, 134.41,
126.32, 126.09, 123.33, 117.77, 65.97, 14.08.
HRMS: m/z [M + H]+ calcd for C12H10BrO5: 311.0914; found:
311.0915.
Allyl 4-Oxo-4H-chromen-3-yl Carbonate (2d)
Yield: 229 mg (93%); Rf = 0.37 (cyclohexane–EtOAc, 7:3).
4-Oxo-4H-chromen-3-yl Benzoate (2j)
Yield: 203 mg (76%); Rf = 0.41 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.30 (dd, J = 7.9, 1.4 Hz, 1 H), 8.26–8.18 (m, 2 H),
8.15 (s, 1 H), 7.81–7.60 (m, 2 H), 7.59–7.34 (m, 4 H).
1H NMR: d = 8.28 (dd, J = 8.0, 1.7 Hz, 1 H), 8.10 (s, 1 H), 7.80–
7.62 (m, 1 H), 7.57–7.37 (m, 2 H), 6.14–5.85 (m, 1 H), 5.54–5.27
(m, 2 H), 4.85–4.70 (m, 2 H).
13C NMR: d = 171.75, 156.18, 152.59, 148.42, 137.66, 134.23,
130.90, 126.35, 125.60, 124.60, 119.86, 118.45, 70.03.
13C NMR: d = 171.83, 164.18, 156.14, 148.55, 137.41, 134.04,
130.61, 128.68, 128.45, 126.30, 125.43, 124.57, 118.38.
HRMS: m/z [M + H]+ calcd for C13H11O5: 247.0601; found:
HRMS: m/z [M + H]+ calcd for C16H11O4: 267.0652; found:
247.0603.
267.0656.
Allyl 4-Oxo-2-phenyl-4H-chromen-3-yl Carbonate (2e)
Yield: 316 mg (98%); Rf = 0.41 (cyclohexane–EtOAc, 7:3).
4-Oxo-2-phenyl-4H-chromen-3-yl Benzoate (2k)
Yield: 329 mg (96%); Rf = 0.41 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.28 (dd, J = 8.0, 1.4 Hz, 1 H), 8.00–7.86 (m, 2 H),
7.80–7.66 (m, 1 H), 7.63–7.38 (m, 5 H), 6.18–5.72 (m, 1 H), 5.57–
5.13 (m, 2 H), 4.87–4.54 (m, 2 H).
13C NMR: d = 172.31, 156.39, 155.69, 152.27, 134.21, 134.08,
131.57, 131.00, 129.76, 128.89, 128.59, 126.22, 125.41, 123.77,
119.40, 118.26, 69.85.
1H NMR: d = 8.29 (dd, J = 8.0, 1.4 Hz, 1 H), 8.25–8.16 (m, 2 H),
8.00–7.88 (m, 2 H), 7.81–7.39 (m, 9 H).
13C NMR: d = 172.30, 164.04, 156.51, 155.83, 134.12, 133.98,
131.39, 130.69, 130.19, 128.85, 128.78, 128.73, 128.45, 126.36,
125.36, 123.84, 118.26.
HRMS: m/z [M + H]+ calcd for C22H15O4: 343.0965; found:
343.0965.
HRMS: m/z [M + H]+ calcd for C19H15O5: 323.0914; found:
323.0918.
2-Bromo-4-oxo-4H-chromen-3-yl Benzoate (2l)
Yield: 251 mg (73%); Rf = 0.48 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.37–8.14 (m, 3 H), 7.82–7.62 (m, 2 H), 7.61–7.40
(m, 4 H).
13C NMR: d = 170.35, 163.18, 156.64, 142.76, 136.35, 134.41,
134.26, 130.79, 128.79, 128.23, 126.72, 126.20, 123.64, 117.94.
Allyl 2-Bromo-4-oxo-4H-chromen-3-yl Carbonate (2f)
Yield: 244 mg (75%); Rf = 0.44 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.17 (dd, J = 7.9, 1.4 Hz, 1 H), 7.77–7.60 (m, 1 H),
7.52–7.36 (m, 2 H), 6.09–5.85 (m, 1 H), 5.57–5.21 (m, 2 H), 4.95–
4.62 (m, 2 H).
13C NMR: d = 170.00, 156.38, 151.48, 142.59, 136.26, 134.47,
130.68, 126.43, 126.17, 123.41, 119.66, 117.84, 70.09.
Synthesis 2011, No. 13, 2159–2164 © Thieme Stuttgart · New York

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D. Dziuba et al.
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HRMS: m/z [M + H]+ calcd for C16H10BrO4: 344.9757; found:
344.9755.
Acknowledgment
The authors thank UNSA, le Conseil Régional PACA, CNRS, and
ANR for financial support and for a doctoral fellowship (ANR) to
D.D.
3-Benzyloxy-4H-chromen-4-one (2m)
Yield: 180 mg (71%); Rf = 0.47 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.30 (dd, J = 7.9, 1.2 Hz, 1 H), 7.71 (s, 1 H), 7.70–
7.58 (m, 1 H), 7.50–7.29 (m, 7 H), 5.17 (s, 2 H).
13C NMR: d = 174.05, 155.84, 144.59, 143.14, 136.43, 133.51,
128.76, 128.47, 128.25, 126.16, 124.76, 124.50, 118.22, 73.14.
HRMS: m/z [M + H]+ calcd for C16H13O3: 253.0859; found:
253.0862.
References
(1) (a) Birt, D. F.; Hendrich, S.; Wang, W. Pharmacol. Ther.
2001, 90, 157. (b) Lee, J.; Park, T.; Jeong, S.; Kim, K.-H.;
Hong, C. Bioorg. Med. Chem. Lett. 2007, 17, 1284.
(c) Prakash, O.; Kumar, R.; Parkash, V. Eur. J. Med. Chem.
2008, 43, 435.
3-Benzyloxy-2-phenyl-4H-chromen-4-one (2n)
Yield: 304 mg (92%); Rf = 0.6 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.29 (dd, J = 8.0, 1.3 Hz, 1 H), 8.06–7.93 (m, 2 H),
7.70–7.56 (m, 1 H), 7.54–7.20 (m, 10 H), 5.12 (s, 2 H).
13C NMR: d = 175.14, 156.42, 155.29, 139.85, 136.61, 133.45,
130.97, 130.62, 128.84, 128.29, 128.21, 128.10, 125.76, 124.71,
124.19, 118.05, 74.08.
HRMS: m/z [M + H]+ calcd for C22H17O3: 329.1172; found:
329.1174.
(2) (a) Klymchenko, A. S.; Demchenko, A. P. Phys. Chem.
Chem. Phys. 2003, 5, 461. (b) Demchenko, A. P. FEBS Lett.
2006, 580, 2951. (c) Choulier, L.; Shvadchak, V. V.;
Naidoo, A.; Klymchenko, A. S.; Mély, Y.; Altschuh, D.
Anal. Biochem. 2010, 401, 188. (d) Shynkar, V. V.;
Klymchenko, A. S.; Kunzelmann, C.; Duportail, G.; Muller,
C. D.; Demchenko, A. P.; Freyssinet, J.-M.; Mely, Y. J. Am.
Chem. Soc. 2007, 129, 2187. (e) Shvadchak, V. V.;
Klymchenko, A. S.; de Rocquigny, H.; Mely, Y. Nucleic
Acids Res. 2009, 37, e25/1. (f) Dyrager, C.; Friberg, A.;
Dahlén, K. Chem. Eur. J. 2009, 15, 9417.
(3) Typical yields range from 25 to 50%. (a) Yongsheng, J.;
Yuanying, J.; Qiuye, W.; Guangquan, L.; Yang, D.;
Wenbao, L. Chinese Patent 101244057, 2008; Chem. Abstr.
2008, 149, 332105. (b) Madhukar, M.; Sawraj, S.; Sharma,
P. D. Eur. J. Med. Chem. 2010, 45, 2591.
3-Benzyloxy-2-bromochromen-4-one (2o)
Yield: 311 mg (94%); Rf = 0.38 (cyclohexane–EtOAc, 7:3).
NMR and MS analytical data fit satisfactorily with the previously
published data.4
(4) Spadafora, M.; Postupalenko, V. Y.; Shvadchak, V. V.;
Klymchenko, A. S.; Mély, Y.; Burger, A.; Benhida, R.
Tetrahedron 2009, 65, 7809.
2-(3,4-Dimethoxyphenyl)-4-oxo-4H-chromen-3-yl 4-Methoxy-
benzoate (2p)
Yield: 419 mg (97%); Rf = 0.26 (cyclohexane–EtOAc, 6:4).
(5) Eckstein, F. Oligonucleotides and Analogues; IRL Press:
NMR and MS analytical data fit satisfactorily with the previously
published data.3a
Oxford, 1991, 313.
(6) PTC conditions were used for the synthesis of alkylated and
glycosylated flavonols, see: (a) Demetzos, C.; Skaltsounis,
A.-L.; Tillequin, F.; Koch, M. Carbohydr. Res. 1990, 207,
131. (b) Gupta, S. C.; Yusuf, M.; Arora, S.; Sharma, S.;
Kamboj, R. C.; Dhawan, S. N. Tetrahedron 2002, 58, 3095.
(c) Li, Z.; Ngojeh, G.; DeWitt, P.; Zheng, Z.; Chen, M.;
Lainhart, B.; Li, V.; Felpo, P. Tetrahedron Lett. 2008, 49,
7243.
(7) (a) McKillop, A.; Fiaud, J. C.; Hug, R. P. Tetrahedron 1974,
30, 1379. (b) Reinholz, E.; Becker, A. Synthesis 1990,
1069. (c) Shirakawa, S.; Yamamoto, K.; Kitamura, M.; Ooi,
T.; Maruoka, K. Angew. Chem. Int. Ed. 2005, 44, 625.
(8) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1999, 246.
(9) (a) Raut, K. B.; Wender, S. H. J. Org. Chem. 1960, 25, 50.
(b) Corvaisier, A.; Tirouflet, J. Compt. Rend. 1960, 251,
1641.
(10) (a) Algar, J.; Flynn, J. P. Proc. Roy. Irish Acad., Sect. B
1934, 42, 1; Chem. Abstr. 1935, 29, 1170. (b) Oyamada, T.
Nippon Kagaku Kaishi 1934, 55, 1256; Chem. Abstr. 1935,
29, 33586. (c) Baker, W. J. Chem. Soc. 1933, 1381.
(d) Mahal, H. S.; Venkataraman, K. J. Chem. Soc. 1934,
1767. (e) Fougerousse, A.; Gonzalez, E.; Brouillard, R.
J. Org. Chem. 2000, 65, 583.
Benzyl 4-Oxo-2-thiophen-2-yl-4H-chromen-3-yl Carbonate (3)
A solution of compound 2c (375 mg, 1 mmol) in anhyd toluene was
degassed three times with argon. Then tributylstannylthiophene
(0.35 mg, 1.1 mmol, 1.1 equiv), Pd(PPh3)4 (58 mg, 5 mol%), and
CuI (19 mg, 10 mol%) were added at once and the reaction mixture
was refluxed for 1 h at 120 °C. The mixture was cooled down to r.t.
and filtered. The organic phase was concentrated in vacuum and pu-
rified by silica gel flash chromatography (eluent: cyclohexane–
EtOAc, 9:1). The product 3 was obtained as a pale yellow solid;
yield: 360 mg (95%); Rf = 0.41 (cyclohexane–EtOAc, 7:3).
1H NMR: d = 8.26 (dd, J = 8.0, 1.5 Hz, 1 H), 7.92 (dd, J = 3.9, 1.2
Hz, 1 H), 7.80–7.30 (m, 9 H), 7.20 (dd, J = 5.0, 3.9 Hz, 1 H), 5.37
(s, 2 H).
13C NMR: d = 171.61, 155.21, 155.21, 152.14, 151.77, 134.72,
134.14, 132.14, 131.74, 131.09, 128.84, 128.77, 128.48, 128.24,
126.16, 125.37, 123.75, 118.02, 71.31.
HRMS: m/z [M + H]+ calcd for C21H15O5S: 379.0635; found:
379.0635.
3-Hydroxy-2-thiophen-2-yl-4H-chromen-3-one (4)
Aqueous ammonia solution (4 mL) was added to a suspension of
compound 3 (200 mg, 0.53 mmol) in EtOH (6 mL). The mixture
was stirred at r.t. for 3 h in a capped flask. After that, it was acidified
with AcOH and concentrated in vacuum to a volume of about 3 mL.
The solution was cooled down to 4 °C. The yellow precipitate was
filtered, washed with H2O (5 mL), and dried under high vacuum in
a desiccator over P2O5; yield: 125 mg (97%).9
(11) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
Synthesis 2011, No. 13, 2159–2164 © Thieme Stuttgart · New York