Synthesis of 7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chromen-6-ones by sequential application of domino reactions of 1,3-bis(silyl enol ethers) with benzopyrylium triflates

Article abstract of DOI:10.1016/j.tet.2006.09.029

The domino, Michael-retro-Michael-aldol, reaction of 2,4-bis(trimethylsilyloxy)penta-1,3-diene with 3-formylchromones afforded 4-(2-hydroxybenzoyl)-2-acetylphenols, which were transformed into 6-(2-hydroxybenzoyl)chromones. The Me₃SiOTf-mediate

Full text of DOI:10.1016/j.tet.2006.09.029

Tetrahedron 62 (2006) 11755–11759
Synthesis of 7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chromen-
6-ones by sequential application of domino reactions of
1,3-bis(silyl enol ethers) with benzopyrylium triflates
Mathias Lubbe,a Bettina Appel,b Anke Flemming,a Christine Fischerc and Peter Langera,c,
*
aInstitut fu€r Chemie, Universita€t Rostock, Albert-Einstein-Str. 3a, D-18059 Rostock, Germany
bInstitut fu€r Biochemie, Universita€t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
cLeibniz-Institut fu€r Katalyse e. V. an der Universita€t Rostock, Albert-Einstein-Str. 29a, D-18059 Rostock, Germany
Received 15 July 2006; revised 28 August 2006; accepted 12 September 2006
Available online 20 October 2006
Abstract—The domino, Michael–retro-Michael–aldol, reaction of 2,4-bis(trimethylsilyloxy)penta-1,3-diene with 3-formylchromones
afforded 4-(2-hydroxybenzoyl)-2-acetylphenols, which were transformed into 6-(2-hydroxybenzoyl)chromones. The Me3SiOTf-mediated
condensation of the latter with 1,3-bis(silyl enol ethers) and subsequent domino ‘retro-Michael–aldol–lactonization’ reaction afforded
7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chromen-6-ones.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the synthesis of 4-(2-hydroxybenzoyl)phenols.9 The
Me3SiOTf-mediated reaction of 1,3-bis(silyl enol ethers)
with chromones provides a facile access to 6H-benzo[c]-
chromen-6-ones.10 Herein, we report the combination of
these two domino reactions based on sequential use of
1,3-bis(silyl enol ethers) at two stages of the synthesis.
This strategy allows a convenient synthesis of 7-hydroxy-
2-(2-hydroxybenzoyl)benzo[c]chromen-6-ones, which com-
bine the structural features of 6H-benzo[c]chromen-6-ones
and 4-(2-hydroxybenzoyl)phenols.
Functionalized 6H-benzo[c]chromen-6-ones (dibenzo[b,d]-
pyran-6-ones) occur in a number of pharmacologically
active natural products, such as autumnariol,1a autumnari-
niol,1b alternariol1c or altenuisol,1d and are specific inhibi-
tors of the growth of endothelic cells2a and oestrogen
receptors.2b Dibenzo[c,d]chromen-6-ones are present in
various natural antibiotics and antitumour agents, such as
the gilvocarcins, chrysomycins and ravidomycins.3 The re-
lated ellagic and coruleoellagic acids are found in plants.4
Functionalized benzophenones also occur in a variety of
natural products and represent important core structures
for the development of pharmaceuticals.5 For example, the
benzophenone phenstatin was discovered as an antitubulin
agent (microtubules represent an important target for anti-
cancer therapy).6 Recently, Hsieh and co-workers reported
that cytotoxic 2-hydroxy- and 2-aminobenzophenones
represent potent antitubulin agents.7
2. Results and discussion
The reaction of 1,3-bis(silyl enol ether) 2 with 3-formyl-
chromones 1a–c afforded the 4-(2-hydroxybenzoyl)phenols
3a–c (Scheme 1, Table 1). The syntheses of 3a9b and
3b,c11 have been previously reported. The formation of
the products can be explained by a domino ‘Michael–
retro-Michael–Aldol’ reaction. Compounds 3a–c were trans-
formed into the novel chromones 4a–c by treatment with
triethyl orthoformate and perchloric acid.12 The Me3SiOTf-
mediated condensation of 4a–c with 1,3-bis(silyl enol
ethers) 5a–d gave the 2,3-dihydrobenzopyrans 6a–e, which
were transformed—by treatment with NEt3—into the novel
7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chromen-6-ones
7a–e. The formation of these products proceeds by a domino
‘retro-Michael–aldol–lactonization’ reaction.10 Notably,
the reaction of 4 with 5 generally afforded the 2,3-dihydro-
pyrans 6 together with a small amount of 7. Therefore, a
mixture of these two compounds was separated from polar
1,3-Bis(silyl enol ethers) represent d4 synthons and can be
regarded as electroneutral equivalents of 1,3-dicarbonyl
dianions.8 In recent years, we have developed a number of
domino reactions of 1,3-bis(silyl enol ethers) with pyrylium
salts. For example, the Me3SiOTf-mediated reaction of
3-formylchromones with 1,3-bis(silyl enol ethers) allows
Keywords: Chromones; Cyclizations; Domino reactions; Oxygen hetero-
cycles; Silyl enol ethers.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412;
e-mail: peter.langer@uni-rostock.de
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.029

11756
M. Lubbe et al. / Tetrahedron 62 (2006) 11755–11759
side-products by chromatography and subsequently treated
with NEt3. Notably, the use of hydroxyl protective groups
was not required for the transformation of 4a–c into 7a–e.
In conclusion, the combination of the Me3SiOTf-mediated
domino Michael–retro-Michael–aldol reaction of 1,3-bis-
(silyl enol ethers) with 3-formylchromones with the domino
‘retro-Michael–aldol–lactonization’ reaction of 1,3-bis(silyl
enol ethers) with chromones allowed an efficient synthesis
of 7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chromen-6-ones.
These products combine the structural features of 6H-
benzo[c]chromen-6-ones and 4-(2-hydroxybenzoyl)phenols.
O
O
R1
H
O
O
Me3SiO
O
R1
H
O
1a-c
Me
i
OSiMe3
Me3SiO
OSiMe3
Me
A
3. Experimental
3.1. General comments
2
Domino 'Michael-Retro-
Michael-aldol' reaction
All solvents were dried by standard methods and all reac-
tions were carried out under an inert atmosphere. For H
1
OH
R1
O
O
O
OH
O
O
and 13C NMR spectra the deuterated solvents indicated
were used. Mass spectrometric data (MS) were obtained
by electron ionization (EI, 70 eV), chemical ionization
(CI, H2O) or electrospray ionization (ESI). For preparative
scale chromatography, silica gel (60–200 mesh) was used.
The melting points are corrected.
ii
Me
OH
R1
3a-c
4a-c
OSiMe3
OR3
Me3SiO
R2
iii
5a-d
3.2. General procedure for the synthesis of
4-(2-hydroxybenzoyl)phenols 3a–c
OH
R1
O
O
O
O
O
iv
To the 3-formylchromone
1 (1.0 equiv) was added
OR3
Me3SiOTf (0.3 equiv) at 20 ꢀC. After stirring for 10 min
CH2Cl2 (8 mL) was added, the solution was cooled to 0 ꢀC
and the 1,3-bis(silyl enol ether) (1.3 equiv) was added. The
mixture was stirred for 12 h at 20 ꢀC and was subsequently
poured into an aqueous solution of hydrochloric acid
(10%). The organic and the aqueous layers were separated
and the latter was extracted with diethyl ether (3ꢁ80 mL).
The combined organic layers were washed with water, dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (silica
gel, hexane/EtOAc¼10:1/3:1).
R2
6a-e
OH
R1
O
O
R2
Domino 'retro-Michael-
aldol-lactonization' reaction
O
OH
O
OR3
B
R2
OH
OH
R1
O
3.2.1. 1-[2-Hydroxy-5-(2-hydroxybenzoyl)phenyl]etha-
none (3a). The synthesis of 3a has been previously
reported.9a Starting with 1a (200 mg, 1.15 mmol),
Me3SiOTf (77 mg, 0.34 mmol) and 1,3-bis(silyl enol ether)
2a (365 mg, 1.49 mmol), 3a was isolated as a colourless
solid (127 mg, 43%), mp 129 ꢀC.
O
O
7a-e
Scheme 1. Synthesis of 7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]chro-
men-6-ones 7a–e: (i) (1) Me3SiOTf (0.3 equiv), 0 ꢀC; (2) CH2Cl2, then 2,
0/20 ꢀC, 12 h; (ii) HC(OEt)3, HClO4 (70%), 0/20 ꢀC, 12–20 h; (iii)
(1) Me3SiOTf (1.3 equiv), 0 ꢀC, 1 h; (2) CH2Cl2, then 5a–d (1.3 equiv),
12 h; (3) HCl (10%); (iv) NEt3, EtOH, 12 h, 20 ꢀC.
3.2.2. 1-[5-Chloro-2-hydroxybenzoyl)-2-hydroxyphenyl]-
ethanone (3b). The synthesis of 3b has been previously re-
ported.11 Starting with 1b (202 mg, 1.10 mmol), Me3SiOTf
(75 mg, 0.33 mmol) and 1,3-bis(silyl enol ether) 2a
(350 mg, 1.43 mmol), 3b was isolated as a colourless solid
(80 mg, 25%), mp 145–146 ꢀC. 1H NMR (250 MHz,
CDCl3): d¼12.71 (s, 1H, OH), 11.64 (s, 1H, OH), 8.19 (d,
Table 1. Products and yields
R1
R2
R3
3 (%)a
4 (%)a
7 (%)a
a
b
c
d
e
H
H
H
H
Me
Et
Et
43
25
29
43
43
52
65
58
52
52
48
70
51
41
23
Cl
Me
H
Me
Me
Et
3
4
4J¼2.1 Hz, 1H, Ar), 7.85 (dd, J¼8.9 Hz, J¼2.1 Hz, 1H,
H
Me
Ar), 7.54 (d, 4J¼2.4 Hz, 1H, Ar), 7.47 (dd, 3J¼8.9 Hz, 4J¼
a
Yields of isolated products.
3
3
2.4 Hz, 1H, Ar), 7.11 (d, J¼8.9 Hz, 1H, Ar), 7.05 (d, J¼
3
8.9 Hz, 1H, Ar), 7.05 (d, J¼8.9 Hz, 1H, Ar), 2.70 (s, 3H,
The core structure of the products 7 contains 20 carbon
atoms out of which 9 carbons are derived from the two
1,3-bis(silyl enol ethers), 10 carbons from the 3-formyl-
chromone and 1 carbon from the orthoformate.
CH3). 13C NMR (75 MHz, CDCl3): d¼204.3 (C]O), 197.7,
165.8 (C–OH), 161.4 (CAr), 137.2, 136.1, 133.3, 131.6
(CH), 128.0, 123.5 (C), 120.3 (CH), 119.6, 119.3 (CAr),
118.8 (CH), 26.7 (CH3).

M. Lubbe et al. / Tetrahedron 62 (2006) 11755–11759
11757
3.2.3. 1-[(2-Hydroxy-5-methylbenzoyl)-2-hydroxyphe-
nyl]ethanone (3c). The synthesis of 3c has been previously
reported.11 Starting with 1c (433 mg, 2.64 mmol),
Me3SiOTf (179 mg, 0.79 mmol) and 1,3-bis(silyl enol ether)
2a (840 mg, 3.43 mmol), 3c was isolated as a colourless
solid (207 mg, 29%), mp 140–141 ꢀC. 1H NMR
(300 MHz, CDCl3): d¼12.66 (s, 1H, OH), 11.58 (s, 1H,
MS (EI, 70 eV): m/z (%)¼302 (M+, 37Cl, 32), 300 (M+,
35Cl, 100), 271 (71), 222 (10), 173 (28), 154 (23). HRMS
(EI, 70 eV): calcd for C16H9ClO4 (M+): 300.01705; found:
300.01839.
3.3.3. 6-(2-Hydroxy-5-methylbenzoyl)chromone (4c).
Starting with 3c (207 mg, 0.81 mmol), triethyl orthoformate
(960 mg, 6.48 mmol) and perchloric acid (70%, 0.15 mL),
4c was isolated (132 mg, 58%) by chromatography (silica
gel, n-heptane/EtOAc) as a colourless solid; Rf 0.38 (n-hep-
tane/EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz): d¼11.64 (s,
1H, OH), 8.50 (d, 4J¼2.1 Hz, 1H, Ar), 8.02 (dd, 3J¼8.5 Hz,
4J¼2.1 Hz, 1H, Ar), 7.91 (d, 3J¼6.1 Hz, 1H, ]CH), 7.61 (d,
3J¼8.5 Hz, 1H, Ar), 7.38–7.29 (m, 2H, Ar), 7.00 (d,
4
OH), 8.19 (d, J¼2.1 Hz, 1H, Ar), 2.28 (s, 3H, CH3), 7.84
3
4
(dd, J¼8.9 Hz, J¼2.1 Hz, 1H, Ar), 7.31–7.37 (m, 2H,
3
3
Ar), 7.08 (d, J¼8.9 Hz, 1H, Ar), 6.99 (d, J¼8.9 Hz, 1H,
Ar), 2.68 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
d¼204.4 (C]O), 198.7, 165.4 (C–OH), 160.9, 137.3,
133.1, 132.4 (CH), 128.9, 127.9, 119.2 (C), 118.6, 118.4,
118.3 (CH), 26.7, 20.5 (CH3).
3
3J¼8.5 Hz, 1H, Ar), 6.42 (d, J¼6.1 Hz, 1H, ]CH), 2.25
3.3. General procedure for the synthesis of chromones
4a–c
(s, 3H, CH3). 13C NMR (CDCl3, 63 MHz): d¼199.4, 176.8
(C]O), 161.2, 158.1 (CAr–O), 155.5, 137.9 (CHAr), 134.9
(CAr), 134.0, 132.7 (CHAr), 128.2 (CAr), 127.5 (CHAr),
124.2 (CAr), 119.0 (CHAr), 118.5 (CAr), 118.4, 113.5
(CHAr), 20.5 (CH3). MS (EI, 70 eV): m/z (%)¼280.0 (M+,
100), 279.0 (83), 251.0 (45), 235.1 (12), 173.0 (14), 135.0
(28). HRMS (EI, 70 eV): calcd for C17H12O4 (M+):
280.07301; found: 280.07231.
To a solution of 4-(2-hydroxybenzoyl)-2-acetylphenols 3
(1.0 equiv) in triethyl orthoformate (10.0 equiv) was added
perchloric acid (60%, 1.3 equiv) at 0 ꢀC. The temperature
was allowed to rise slowly to 20 ꢀC and the solution was
stirred for additional 12 h. The product was separated from
the solution by filtration and purified by column chromato-
graphy (silica gel, n-heptane/EtOAc¼9:1).
3.4. General procedure for the synthesis of 7-hydroxy-2-
(2-hydroxybenzoyl)benzo[c]chromen-6-ones 7a–e
3.3.1. 6-(2-Hydroxybenzoyl)chromone (4a). Starting with
3a (292 mg, 1.14 mmol), triethyl orthoformate (1.35 g,
1.49 mL, 9.08 mmol) and perchloric acid (60%, 240 mg,
0.24 mL, 1.47 mmol), 4a was isolated (158 mg, 52%)
by chromatography (silica gel, hexanes/EtOAc¼5:1) as a
To chromone 4 (1.0 equiv) was added Me3SiOTf (1.3 equiv)
at 20 ꢀC and the mixture was stirred for 1 h at 20 ꢀC. Subse-
quently, dichloromethane (8 mL/mmol) was added and the
solution was cooled to 0 ꢀC. The 1,3-bis(silyl enol ether) 3
(1.3 equiv) was added, the temperature was allowed to
warm slowly to 20 ꢀC and the solution was stirred for
12 h. To the mixture was added hydrochloric acid (10%),
the organic and the aqueous layers were separated and the
latter was extracted with dichloromethane (3ꢁ50 mL). The
combined organic layers were dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. The residue was
purified by a rapid flash chromatography (silica gel, n-hep-
tane/EtOAc¼5:1) to remove polar side-products. The 2,3-
dihydrobenzopyran 6 (together with some amount of 7)
was dissolved in dry ethanol (10 mL/mmol), triethylamine
(3.0 equiv) was added and the solution was stirred for 12 h
at 20 ꢀC. To the solution was added hydrochloric acid
(10%) and diethyl ether. After stirring for 30 min, the
organic and the aqueous layers were separated and the latter
was extracted with diethyl ether (3ꢁ80 mL). The combined
organic layers were dried (Na2SO4), filtered and the filtrate
was concentrated in vacuo. The residue was purified by chro-
matography (silica gel, n-heptane/EtOAc¼20:1) to give the
product 7.
1
yellow solid, mp 172 ꢀC. H NMR (DMSO-d6, 300 MHz):
3
d¼10.27 (s, 1H, OH), 8.36 (d, J¼6.2 Hz, 1H, CH), 8.27
4
3
4
(d, J¼2.2 Hz, 1H, Ar), 8.16 (dd, J¼8.8 Hz, J¼2.3 Hz,
3
1H, Ar), 7.78 (d, J¼8.6 Hz, 1H, Ar), 7.47 (m, 1H, Ar),
3
4
7.38 (dd, J¼7.6 Hz, J¼1.6 Hz, 1H, Ar), 6.98 (m, 2H,
Ar), 6.42 (d, J¼6.2 Hz, 1H, CH). 13C NMR (DMSO-d6,
3
75.5 MHz): d¼195.3, 176.1 (C]O), 158.3 (CAr), 157.4
(CHAr), 156.4, 134.3 (CAr), 133.9, 133.3, 130.2, 127.3
(CHAr), 124.8, 123.7 (CAr), 119.3, 119.2, 116.7, 112.6
(CHAr). IR (KBr, cmꢂ1): ~n ¼ 3426 (m), 3258 (w), 3175
(w), 3086 (m), 2928 (m), 1656 (s), 1616 (s), 1481 (s),
1443 (s), 1340 (s), 1300 (s), 1247 (s), 1175 (m), 1137 (m),
1027 (w), 959 (w), 846 (m), 800 (w), 762 (m), 724 (w),
624 (w), 545 (m). UV–vis (CH3CN, nm): lmax (log 3): 338
(3.73), 305 (3.88), 242 (4.35), 216 (4.38). MS (EI, 70 eV):
m/z (%)¼266 (M+, 100), 237 (56), 221 (10), 173 (17), 145
(14), 121 (40), 93 (11), 90 (16), 66 (18). Anal. C16H10O4
(266.3) calcd: C, 72.18; H, 3.79; found: C, 71.92; H, 3.65.
3.3.2. 6-(5-Chloro-2-hydroxybenzoyl)chromone (4b).
Starting with 3b (80 mg, 0.28 mmol), triethyl orthoformate
(332 mg, 2.24 mmol) and perchloric acid (70%, 0.05 mL),
4b was isolated (54 mg, 65%) as a yellow solid; Rf 0.33
(n-heptane/EtOAc¼1:1). 1H NMR (CDCl3, 250 MHz):
3.4.1. 7-Hydroxy-2-(2-hydroxybenzoyl)benzo[c]chro-
men-6-one (7a). Starting with 4a (252 mg, 0.95 mmol),
Me3SiOTf (274 mg, 0.22 mL, 1.24 mmol) and 5a (340 mg,
1.24 mmol) (first step), and triethylamine (435 mg,
4.3 mmol) and ethanol (10 mL) (second step), 7a was iso-
4
d¼11.69 (s, 1H, OH), 8.50 (d, J¼2.4 Hz, 1H, Ar), 8.00
3
4
3
(dd, J¼8.5 Hz, J¼2.4 Hz, 1H, Ar), 7.92 (d, J¼6.1 Hz,
3
1
1H, ]CH), 7.63 (d, J¼8.5 Hz, 1H, Ar), 7.51–7.46 (m,
lated (151 mg, 48%) as a colourless solid, mp 220 ꢀC. H
3
3
2H, Ar), 7.06 (d, J¼8.5 Hz, 1H, Ar), 6.42 (d, J¼6.1 Hz,
1H, ]CH). 13C NMR (CDCl3, 63 MHz): d¼198.6, 176.6
(C]O), 161.7, 158.4 (CAr–O), 155.5, 136.7 (CHAr), 134.1
(CAr), 133.8, 131.9, 127.6 (CHAr), 124.4 (CAr), 123.7 (CAr),
120.3 (CHAr), 119.5 (CAr), 119.3 (CHAr), 113.6 (CHAr).
NMR (CDCl3, 300 MHz): d¼11.85 (s, 1H, OH), 11.24 (s,
1H, OH), 8.41 (d, 4J¼1.9 Hz, 1H, Ar), 7.83 (dd, 3J¼
4
3
8.5 Hz, J¼2.0 Hz, 1H, Ar), 7.77 (t, J¼8.1 Hz, 1H, Ar),
3
7.59 (m, 3H, Ar), 7.51 (d, J¼8.5 Hz, 1H, Ar), 7.15 (m,
2H, Ar), 6.93 (m, 1H, Ar). 13C NMR (CDCl3, 75.5 MHz):

11758
M. Lubbe et al. / Tetrahedron 62 (2006) 11755–11759
d¼199.7 (C]O), 164.8, 163.3, 162.6, 152.7 (CAr–O), 137.7,
136.8 (CHAr), 134.9, 134.3 (CAr), 133.1, 131.4, 125.1, 119.0
(CHAr), 118.9 (CAr), 118.8 (CHAr), 118.6 (CAr), 117.9,
117.5, 112.6 (CHAr), 106.1 (CAr). IR (KBr, cmꢂ1):
~n ¼ 3122 (m), 3052 (m), 1683 (s), 1626 (s), 1593 (s), 1484
(m), 1447 (s), 1347 (m), 1302 (m), 1276 (s), 1243 (s),
1206 (s), 1139 (m), 1072 (m), 994 (w), 840 (w), 760 (m),
710 (m). UV–vis (CH3CN, nm): lmax (log 3): 349 (4.09),
338 (4.10), 261 (4.37), 231 (4.42), 217 (4.39). Fluorescence
(CH3CN, nm): Flmax (lEx): 485 (340). MS (EI, 70 eV): m/z
(%)¼332 (M+, 8), 256 (71), 241 (10), 212 (18), 163 (24), 148
(21), 121 (100), 105 (22), 66 (31).
solid, mp 190–191 ꢀC; Rf 0.51 (n-heptane/EtOAc¼1:1). 1H
NMR (CDCl3, 250 MHz): d¼11.87 (s, 1H, OH), 11.47 (s,
1H, OH), 8.38 (d, 4J¼2.1 Hz, 1H, Ar), 7.79 (dd,
4
3J¼8.5 Hz, J¼2.1 Hz, 1H, Ar), 7.65–7.46 (m, 5H, Ar),
3
3
7.13 (d, J¼8.5 Hz, 1H, Ar), 6.93 (t, J¼8.5 Hz, 1H, Ar),
2.38 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz): d¼199.8
(C]O), 165.2, 163.3, 160.6, 152.4 (CAr–O), 138.6, 136.7
(CHAr), 134.7, 134.1 (CAr), 133.1 (CHAr), 131.7 (CAr),
130.7 (CHAr), 127.2 (CAr), 124.7 (CHAr), 118.9 (CAr),
118.9 (CHAr), 118.7, 117.7, 111.9 (CHAr), 105.3 (CAr),
15.8 (CH3). IR (Nujol, cmꢂ1): ~n ¼ 1685 (s), 1623 (s),
1603 (s). MS (EI, 70 eV): m/z (%)¼346 (M+, 100), 345
(35), 266 (27), 265 (25), 226 (82), 121 (44). HRMS (EI,
70 eV): calcd for C21H14O5 (M+): 346.08358; found:
346.08421.
3.4.2.
7-Hydroxy-2-(5-chloro-2-hydroxybenzoyl)-
[c]chromen-6-one (7b). Starting with 4b (54 mg,
0.18 mmol), Me3SiOTf (51 mg, 0.23 mmol) and 5b
(60 mg, 0.23 mmol) in CH2Cl2 (1.8 mL) (first step), and trie-
thylamine (85 mg, 0.85 mmol) in ethanol (1.5 mL) (second
step), 7b was isolated (46 mg, 70%) as a slightly yellow
3.4.5. 8-Ethyl-7-hydroxy-2-(2-hydroxybenzoyl)benzo[c]-
chromen-6-one (7e). Starting with 4a (267 mg, 0.5 mmol),
Me3SiOTf (145 mg, 0.65 mmol) and 5d (144 mg,
0.5 mmol) in CH2Cl2 (2.5 mL) (first step), and triethylamine
(202 mg, 2.0 mmol) and ethanol (5 mL) (second step), 7e
was isolated (40 mg, 23%) as a colourless solid, mp 160–
161 ꢀC; Rf 0.28 (n-heptane/EtOAc¼9:1). 1H NMR
(CDCl3, 250 MHz): d¼11.86 (s, 1H, OH), 11.47 (s, 1H,
1
solid; Rf 0.66 (n-heptane/EtOAc¼1:1). H NMR (CDCl3,
250 MHz): d¼11.72 (s, 1H, OH), 11.22 (s, 1H, OH), 8.40
(d, 4J¼2.1 Hz, 1H, Ar), 7.84–7.75 (m, 2H, Ar), 7.64 (d, 3J¼
8.2 Hz, 1H, Ar), 7.57–7.49 (m, 3H, Ar), 7.17 (d, 3J¼8.2 Hz,
3
1H, Ar), 7.09 (d, J¼8.2 Hz, 1H, Ar). 13C NMR (DMSO,
4
63 MHz): d¼193.7 (C]O) 163.6, 161.1, 154.7, 152.9
(CAr–O), 137.8 (CHAr), 134.2, 133.9, 133.7 (CAr), 132.4,
131.8, 129.1 (CHAr), 126.8 (CAr), 125.0 (CHAr), 122.8
(CAr), 118.4 (CHAr), 118.0 (CAr), 117.6, 116.8, 113.1
(CHAr). MS (EI, 70 eV): m/z (%)¼368 (M+, 37Cl, 15), 366
(M+, 35Cl, 46), 239 (13), 212 (100), 155 (17). HRMS (EI,
70 eV): calcd for C20H11CO5 (M+): 366.02895; found:
366.02788.
OH), 8.34 (s, 1H, Ar), 8.36 (d, J¼2.1 Hz, 1H, Ar), 7.78
3
4
(dd, J¼8.5 Hz, J¼2.1 Hz, 1H, Ar), 7.65–7.48 (m, 4H,
3
Ar), 7.12 (d, J¼8.5 Hz, 1H, Ar), 6.92 (m, 1H, Ar), 2.78
(q, 3J¼7.3 Hz, 2H, CH2CH3), 1.28 (t, 3J¼7.3 Hz, 3H,
CH2CH3). 13C NMR (CDCl3, 75 MHz): d¼199.8 (C]O),
165.2, 163.3, 160.3, 152.4 (CAr–O), 137.0, 136.7 (CHAr),
134.7 (CAr), 133.1 (CHAr), 133.0 (CAr), 131.6 (CAr), 130.8,
124.7 (CHAr), 118.9 (CAr), 118.9, 118.7, 117.7, 112.1
(CHAr), 105.4 (CAr), 2.9 (CH2CH3), 13.5 (CH2CH3). MS
(EI, 70 eV): m/z (%)¼360 (M+, 100), 345 (98), 240 (49),
225 (56), 121 (38). HRMS (EI, 70 eV): calcd for
C22H16O5 (M+): 360.0980; found: 360.0992.
3.4.3. 7-Hydroxy-2-(2-hydroxy-5-methylbenzoyl)benzo-
[c]chromen-6-one (7c). Starting with 4c (130 mg,
0.46 mmol), Me3SiOTf (133 mg, 0.60 mmol), 5b (156 mg,
0.60 mmol) in CH2Cl2 (8 mL) (first step), and triethylamine
(218 mg, 2.15 mmol) in ethanol (5 mL) (second step), 7c
was isolated (80 mg, 51%) as a colourless solid, mp
213–214 ꢀC; Rf 0.70 (n-heptane/EtOAc¼1:1). 1H NMR
(CDCl3, 250 MHz): d¼11.67 (s, 1H, OH), 11.25 (s, 1H,
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
is gratefully acknowledged.
4
OH), 8.39 (d, J¼2.1 Hz, 1H, Ar), 7.83–7.79 (m, 1H, Ar),
3
3
7.75 (d, J¼8.5 Hz, 1H, Ar), 7.63 (d, J¼8.9 Hz, 1H, Ar),
3
7.51 (d, J¼8.9 Hz, 1H, Ar), 7.40–7.34 (m, 2H, Ar), 7.15
4
3
3
References and notes
(dd, J¼2.1 Hz, J¼8.5 Hz, 1H, Ar), 7.03 (d, J¼8.5 Hz,
1H, Ar), 2.27 (s, 3H, CH3). 13C NMR (CDCl3, 75 MHz): d¼
199.6 (C]O), 164.8, 162.6, 161.2, 152.5 (CAr–O), 137.8,
137.7 (CHAr), 135.0, 134.3, 133.2 (CAr), 132.7, 131.3
(CHAr), 128.2 (CAr), 124.9, 118.6, 118.5, 117.7 (CHAr),
117.4 (CAr), 112.5 (CHAr), 106.1 (CAr), 20.5 (CH3). IR
(KBr, cmꢂ1): ~n ¼ 3441 (s, br), 3079 (w), 3058 (w), 2925
(m), 2855 (m), 1691 (s), 1629 (s), 1592 (s). MS (EI,
70 eV): m/z (%)¼346.0 (M+, 15), 311.0 (10), 265.0 (37),
251.0 (24), 221.0 (27), 178.0 (25), 134.0 (21). HRMS (EI,
70 eV): calcd for C21H14O5 (M+): 346.0836; found:
346.0842.
1. (a) Sidwell, W. T. L.; Fritz, H.; Tamm, C. Helv. Chim. Acta
1971, 54, 207; (b) Tamm, C. Arzneim.-Forsch. 1972, 22,
1776; (c) Raistrick, H.; Stilkings, C. E.; Thomas, R.
Biochemistry 1953, 55, 421; (d) Pero, R. W.; Harvan, D.;
Blois, M. C. Tetrahedron Lett. 1973, 14, 945.
2. (a) Schmidt, J. M.; Tremblay, G. B.; Page, M.; Mercure, J.;
Feher, M.; Dunn-Dufault, R.; Peter, M. G.; Redden, P. R.
J. Med. Chem. 2003, 46, 1289; (b) Pandey, J.; Jha, A. K.;
Hajela, K. Bioorg. Med. Chem. 2004, 12, 2239.
3. (a) McGee, L. R.; Confalone, P. N. J. Org. Chem. 1988, 53,
3695; (b) Hart, D. J.; Mannino, A. Tetrahedron 1996, 52,
3841; (c) Fischer, C.; Lipata, F.; Rohr, J. J. Am. Chem. Soc.
2003, 125, 7818 and references cited therein.
4. (a) Sayer, J. M.; Haruhiko, Y.; Wood, A. W.; Conney, A. H.;
Jerina, D. M. J. Am. Chem. Soc. 1982, 104, 5562; (b)
Geevanada, Y. A.; Gunawardana, P.; Kumar, N. S.;
Sultanbawa, M. U. S. Phytochemistry 1979, 18, 1017.
3.4.4. 7-Hydroxy-2-(2-hydroxybenzoyl)-8-(methyl)benzo-
[c]chromen-6-one (7d). Starting with 4a (360 mg,
1.35 mmol), Me3SiOTf (391 mg, 1.76 mmol) and 5c
(385 mg, 1.76 mmol) in CH2Cl2 (7 mL) (first step), and tri-
ethylamine (545 mg, 5.4 mmol) in ethanol (20 mL) (second
step), 7d was isolated (192 mg, 41%) as a slightly yellow

M. Lubbe et al. / Tetrahedron 62 (2006) 11755–11759
11759
5. For salicylic esters and salicylic glycosides (e.g., salicortin),
see for example: Ro€mpp Lexikon Naturstoffe; Steglich, W.,
Fugmann, B., Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
6. Pettit, G. R.; Toki, B.; Herald, D. L.; Verdier-Pinard, P.; Boyd,
M. R.; Hamel, E.; Pettit, R. K. J. Med. Chem. 1998, 41, 1688.
7. (a) Liou, J.-P.; Chang, J.-Y.; Chang, C.-W.; Chang, C.-Y.;
Mahindroo, N.; Kuo, F.-M.; Hsieh, H.-P. J. Med. Chem. 2004,
47, 2897; (b) Liou, J.-P.; Chang, C.-W.; Song, J. S.; Yang,
Y. S.; Yeh, C. F.; Tseng, H. Y.; Lo, Y. K.; Chang, C.-L.;
Chang, C.-M.; Hsieh, H.-P. J. Med. Chem. 2002, 45, 2556.
8. For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
Synthesis 2002, 441.
9. (a) Langer, P.; Appel, B. Tetrahedron Lett. 2003, 44, 7921; (b)
Nguyen, V. T. H.; Appel, B.; Langer, P. Tetrahedron 2006, 62,
7674; (c) Appel, B.; Rotzoll, S.; Kranich, R.; Reinke, H.;
Langer, P. Eur. J. Org. Chem. 2006, 3638.
10. (a) Langer, P.; Saleh, N. N. R.; Freifeld, I. Chem. Commun.
2002, 168; (b) Appel, B.; Saleh, N. N. R.; Langer, P.
Chem.—Eur. J. 2006, 12, 1221; (c) Ullah, E.; Appel, B.;
Fischer, C.; Langer, P. Tetrahedron 2006, 62, 9694.
11. Banyopadhyay, C.; Sur, K. R.; Patra, R. J. Chem. Res., Synop.
1998, 12, 802.
12. Jean, J. C.; Wise, L. D.; Heffner, T. G.; Pugsley, T. A.; Meltzer,
L. T. J. Med. Chem. 1991, 34, 248.