Successive Michael reactions on chromone derivatives with dimethyl 1,3-acetonedicarboxylate: one-pot synthesis of functionalized benzophenones, benzo[c]chromones and hydroxybenzoylfuroates

Article abstract of DOI:10.1016/j.tet.2008.10.023

Chromones were reacted with dimethyl acetonedicarboxylate in the presence of DBU in THF at room temperature to furnish good yields of products, their structure depending on the substituent at 3-position. Unsubstituted chromones lead to methyl 7-hydroxy-6-

Full text of DOI:10.1016/j.tet.2008.10.023

Tetrahedron 64 (2008) 11611–11617
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Successive Michael reactions on chromone derivatives with
dimethyl 1,3-acetonedicarboxylate: one-pot synthesis of functionalized
benzophenones, benzo[c]chromones and hydroxybenzoylfuroates
,
Michael A. Terzidis a, Constantinos A. Tsoleridis a, Julia Stephanidou-Stephanatou a
,
*
Aristides Terzis b, Catherine P. Raptopoulou b, Vassilis Psycharis b
a Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
b X-Ray Laboratory, NCR ‘Democritos’, Athens, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Chromones were reacted with dimethyl acetonedicarboxylate in the presence of DBU in THF at room
temperature to furnish good yields of products, their structure depending on the substituent at 3-
position. Unsubstituted chromones lead to methyl 7-hydroxy-6-oxo-6H-benzo[c]chromone-8-carboxyl-
ates 2, whereas by using 3-bromochromone, the methyl furoate 3c along with the unexpected
furylcyclopropyl-chromene carboxylate 4c was isolated. Finally, from 3-formyl-chromones functionalized
benzophenones 5 were isolated, in good yields. Plausible mechanisms are proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 August 2008
Received in revised form
25 September 2008
Accepted 9 October 2008
Available online 14 October 2008
Keywords:
Acetonedicarboxylate
3-Formyl-chromone
Benzo[c]chromones
Benzoyl-furoates
1. Introduction
presence of piperidine, leading to isolation of benzopyranopyri-
dines, was reported.16 In addition, it was reported that 3-formyl-
Besides forming the basic nucleus of an entire class of natural
products, i.e., flavones,1 the chromone moiety forms the important
component of pharmacophores of a large number of molecules of
medicinal significance.2 Consequently, considerable attention is
being devoted to isolation from natural resources, chemistry, and
synthesis of chromone derivatives, and evaluation of their biological
activity with emphasis on their potential medicinal applications.2–4
Moreover, chromones can be readily converted into a broad range of
heterocyclic systems, e.g., xanthones5 and pyranobenzopyranones6
by cycloaddition strategies, pyrazolopyrimidines,7 pyridopyri-
midines,8 pyrimidopyrimidines,9 benzopyranobenzothiazepines,
-oxazepines, -diazepines,10 furobenzopyranones,11 o-hydroxyphenyl
substituted pyrazoles,12 and pyrimidines13,14 through reaction with
several nucleophiles, and particularly bis-nucleophiles.
chromones react with various active methylene compounds in
basic media to produce mainly Knoevenagel-type condensation
products.17 Recently, the reaction between the chromone and the
dianion of ethyl acetoacetate or its electroneutral equivalent, 1,3-
bis(trimethylsilyloxy)-1,3-butadiene, was attempted.18 Eventually,
through a three-step reaction sequence involving activation of
the chromone moiety through formation of benzopyrylium
triflates, their subsequent reaction with 1,3-bis(trimethylsilyloxy)-
1,3-butadienes and finally ring closure with triethylamine,
benzo[c]chromen-6-ones were isolated, instead of the expected
1-hydroxy-xanthones. Moreover, the reaction between the 3-for-
myl-chromone with the dianion of benzoylacetone was found to
result to the formation of complex reaction mixtures.19 However,
functionalized benzophenones were isolated through formation of
benzopyrylium triflates and subsequent reaction with 1,3-bis-
silyl-enol ethers19 or by domino ‘Michael–retro-Michael–Wittig’
reactions of dioxobutylidenetriphenylphosphoranes with 3-for-
myl-chromones.20
The reaction between 3-acyl-2-methylthio-chromones and
acetylacetone or diethyl 1,3-acetonedicarboxylate in the presence
of potassium tert-butoxide leading to xanthone derivatives has
been studied by Eiden et al.15 in 1984. Shortly after, the reaction
of 3-cyano-chromones with acetonedicarboxylates in the
Functionalized benzophenones are of considerable interest as
pharmacologically relevant natural products and natural product
analogs and represent21,22 versatile synthetic building blocks.
Functionalized benzophenones are also used as photosensitizers23
and as active ingredients of commercial agents, which protect the
* Corresponding author. Tel.: þ30 2310 997831; fax: þ30 2310 997679.
E-mail address: ioulia@chem.auth.gr (J. Stephanidou-Stephanatou).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.023

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M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
skin or color against UV irradiation.24 Their classical synthesis
through Friedel–Crafts acylation25 leads frequently to unsatis-
factory results, especially when it is applied to substituted de-
rivatives. Other benzophenone syntheses rely on the reaction of
organometallic reagents with aldehydes and subsequent oxidation.
A more recent modification of this approach involves the SmI2
mediated reaction of benzaldehydes with benzylhalides and
subsequent oxidation.26
On the other hand, benzo[c]chromen-6-ones are present in
a number of pharmacologically relevant natural products such as
autumnariol,27 autumnariniol,28 alternariol,29and altenuisol.30
Benzo[c]chromen-6-ones are specific inhibitors of the growth of
endothelic cells31 and represent estrogen receptors.32 Therefore,
various methods have been employed for their synthesis, such as
cyclization of bromobenzoic acids with phenols,33 palladium
catalyzed coupling reactions,34 Suzuki reactions,35 and recently
retro-Michael aldol lactonization reactions.18
additional equivalent of chromone 1c and DBU at room temper-
ature, proving thus that 3c constitutes the intermediate for the
formation of 4c (see also proposed mechanism).
Finally, from the 3-formyl-chromones (1d–1g) functionalized
hydroxy-benzophenones 5 were isolated (Scheme 1), instead of the
expected Knoevenagel-type condensation products.17
For the formation of products 2 a plausible mechanism depicted
in Scheme 2 can be proposed. The reaction is most probably initi-
ated by an attack of the base-activated nucleophilic acetonedi-
carboxylate to the C-2 chromone carbon, being a Michael acceptor,
followed by chromone ring opening, forming thus the open chain
intermediate 6a. Subsequent ring closure, via an intramolecular
Michael reaction (path a), leads to intermediate 7, from which 8b
can be formed by loss of methanol. Dehydration to 9 and tauto-
merization of the b-keto-ester group leads to the isolated lactone 2.
To the contrary, the formation of a 10-membered ring 10 (path b) by
lactonization of the intermediate 6, followed by a subsequent
transannular aldol condensation, appears to be less likely (Scheme
2). PM3 MO calculations predict that the described transformations
7a to 7b, and 9 to 2a (path a) are energetically favored and also that
path a is favored over path b.
In the case of the 3-bromo-substituted chromone 1c, Michael
attack on C-2 forms the analogous enolate intermediate 11 from
which, most probably through a second intramolecular Michael
attack of the enolate oxygen to the bromine bearing carbon (O-al-
kylation), 12 can be formed. Subsequent pyrane ring opening,
results to the isolated furan derivative 3c (Scheme 3). However, in
the presence of an excess of DBU, a new enolate anion 13 is most
probably formed, which reacts with a second bromochromone
molecule to give 14. Through [1,3-H] shift to intermediate 15 and
nucleophilic attack at the bromine bearing carbon, the isolated
product 4c is formed containing a three-membered ring. The for-
mation of the cyclopropyl derivative 4c at room temperature is
remarkable and, needless to note, unexpected.
In the light of this literature information, we speculated that the
synthesis of benzo[c]chromones and functionalized benzophe-
nones would be possible by a one-pot reaction from readily
available starting materials, namely through Michael reaction
between chromones and 3-formyl-chromones with dimethyl
acetonedicarboxylate.
2. Results and discussion
When chromones 1a and 1b were allowed to react with
equimolar amounts of dimethyl acetonedicarboxylate in the
presence of 1.3 equiv of the base 1,8-diazabicyclo[5.4.0]undecane-
7 (DBU) in the aprotic non-polar solvent THF at room temperature
for 2 h the dibenzopyrane derivatives 2a and 2b were isolated in
good yields (50–65%, Scheme 1). However, chromones bearing
a methyl group at C-2, namely 2-methylchromone and 6-bromo-
2-methylchromone, failed to undergo the above reaction even
with heating for extended reaction periods. To the contrary, when
the reaction was repeated36 with 3-bromochromone (1c), ap-
proximately 10% of the starting material 1c was recovered along
with the furan derivative 3c isolated in 19% yield, whereas a
highly unexpected product containing a cyclopropyl ring, namely
the furylcyclopropyl-chromene carboxylate 4c, was the main re-
action product in 42% yield (Scheme 1). When the same reaction
was repeated at room temperature with 2 equiv of DBU, complete
conversion of the chromone 1c was observed. In this case the
yield of 4c was increased to 65%, whereas 3c was formed in only
6% yield. In addition, it was possible to convert the furan de-
rivative 3c to the cyclopropyl derivative 4c by reacting it with an
Finally, in the case of formyl-chromones the corresponding
enolate anion 16, formed at the side-chain methylene carbon, leads
through a second intramolecular Michael reaction to the formation
of the new six-membered ring (intermediate 17). By loss of water to
18 and tautomerization, the isolated products 5 (Scheme 4) are
formed.
2.1. Structure assignments of the new compounds
The assigned molecular structures of the new compounds 2, 4,
and 5 were based on rigorous spectroscopic analysis including IR,
NMR (1H, 13C, COSY, NOESY, HETCOR and COLOC), MS, and
4
R1
COOMe
R1
R2
R1
O
O
7
COOMe
2
O
H
3
6
R2
H
R2
3
6''
1''
6'
1'
3'
4
5
4
5
4'
5'
OH
1
CH2COOMe
+
2
1
2'
3'
O
3''
O
7
10
2'
2''
O
i
CO
COOMe
O
9
O
O
H
O
2a-b
3c
OMe
H
i
4c
8
5
R2
R1
O
O
O
O
O
2
+
R1
COOMe
OH
R3
i
3
MeO
OMe
3
R2
6'
1'
4
1
3'
5
COOMe
1
2'
O
6
O
H
1a R1= R2= R3= H
1d R1= R2= H,
R3= CHO
5d-g
1b R1= Cl, R2= R3= H
1c R1= R2= H, R3= Br
1e R1= Me, R2= H, R3= CHO
1f R1= Cl, R2= H, R3= CHO
1g R1= Cl, R2= Me, R3= CHO
(i) DBU, THF, rt, 2-3 h
Scheme 1. Reaction between differently 3-substituted chromones with dimethyl acetonedicarboxylate under the same reaction conditions.

M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
11613
COCH2COOMe
R2
R1
O
O
R2
R1
O
DBU
THF
COOMe
MeO
OMe
+
O
O
O
O
O
1a-b
COOMe
MeO
path b
C
CH2
C
O
HC
H
O
O
C
O
O
R2
R1
R2
R1
R2
R1
O
O
path a
DBU
path b
H
C
CH2OOMe
CH2OOMe
CH
6a
COOMe
CH=CH
O
O
O
6b
10
DBU
O
OH
R2
R1
COOMe
O
O
R2
R1
R2
R1
O
O
O
O
O
COOMe
COOMe
O
O
COOMe
7a
8a
R2
R1
R2
R1
O
O
R2
R1
O
O
O
R2
R1
O
O
O
CO OMe
O
-CH3OH
-H2O
O
OH
HO
8b
Scheme 2. Plausible reaction mechanism proposed for the formation of compounds 2.
HO
COOMe
COOMe
COOMe
COOMe
7b
9
2a-b
elemental analysis data. In Figure 1 the COLOC correlations of
protons with carbons via 2J and 3J coupling constants for com-
pounds 2a, 3c, and 4c are depicted.
In addition, since the formation of a cyclopropane ring at room
temperature seemed most improbable the structure of 4c was
undoubtedly elucidated by crystal structure analysis38 (Fig. 2). The
structure of 5d was also confirmed by crystal structure analysis38
(Fig. 3).
triflates19 or dioxobutylidenetriphenylphosphoranes with 3-for-
myl-chromones.20 Finally, by using 3-bromochromone the un-
expected and otherwise inaccessible furylcyclopropyl-chromene
carboxylate was synthesized along with hydroxybenzoylfuran.
4. Experimental
4.1. General
3. Conclusions
Melting points were measured on a Kofler hot-stage and are
uncorrected. Column chromatography was carried out using
Merck silica gel. TLC was performed using precoated silica gel
glass plates 0.25 mm containing fluorescent indicator UV254 pur-
chased from Macherey–Nagel using a 3:1 mixture of petroleum
ether–ethyl acetate. Petroleum ether refers to the fraction boiling
between 60 and 80 ꢀC. NMR spectra were recorded at room
temperature (rt) on a Bruker AM 300 spectrometer at 300 MHz
for 1H and 75 MHz for 13C, using CDCl3 as solvent. Chemical shifts
In conclusion, we have shown that from cheap, easily accessible
starting materials, namely chromones, dimethyl acetonedicarboxy-
late, and DBU, and very mild reaction conditions, very interesting
products can be isolated in good yields through a one-step reaction,
the type of the isolated product depending on the substituent at
chromone 3-position. Moreover, the present work demonstrates
the versatility of chromones in bringing about one-pot synthetic
procedures.
are expressed in
d values (ppm) relative to TMS as internal
By using unsubstituted chromones 7-hydroxy-6-oxo-6H-ben-
zo[c]chromene-8-carboxylates are formed. Analogous compounds
are reported in the literature though a three-step reaction se-
quence18 involving the formation of benzopyrylium triflates and
subsequent reaction with 1,3-bis(trimethylsilyloxy)-1,3-butadiene.
By applying the same reaction conditions on 3-formyl-chromones
functionalized benzophenones (2-hydroxybenzoylphenols) were
isolated. Again, analogous products are reported from reactions
either between 1,3-bis-silylenol ethers and benzopyrylium
standard for 1H and relative to TMS (0.00 ppm) or to CDCl3
(77.05 ppm) for 13C NMR spectra. Coupling constants nJ are
reported in Hertz. Second order 1H spectra in the aromatic region,
where it was possible, were analyzed by simulation.37 IR spectra
were recorded on a Perkin–Elmer 297 spectrometer or on a Per-
kin–Elmer 1600 series FTIR spectrometer and are reported in
wave numbers (cmꢁ1). Low-resolution electron impact mass
spectra were recorded on a 6890N GC/MS system (Agilent Tech-
nology) and elemental analyses performed with a Perkin–Elmer

11614
M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
COOMe
C
COOMe
O
O
O
O
O
R
DBU
C
R
MeO
OMe
+
THF
O
Br
Br
Br
O
O
O
O
O
R = CH2COOMe
1c
COOMe
C
COOMe
R
COOMe
COOMe
CH2COOMe
O
O
O
O
O
R
+H
DBU
-Br
R
O
O
O
Br
O
H
O
O
O
H
11
12
3c
COOMe
COOMe
COOMe
O
[1,3]-H Shift
DBU
CHCOOMe
+
CH
Br
O
O
Br
O
O
O
O
O
O
O
H
H
1c
13
14
COOMe
H
COOMe
COOMe
O
H
C
Br
O
O
O
CO
O
O
O
O
O
O
OMe
H
H
4c
15
Scheme 3. Plausible reaction mechanism proposed for the formation of compounds 3c and 4c.
2400-II CHN analyzer. Structural assignments of the derived
compounds were established by analysis of their IR, MS, and NMR
spectra (1H, 13C, COSY, NOESY, HETCOR, and COLOC).
DBU (0.20 mL, 1.3 mmol) was added via a syringe at room tem-
perature. Stirring was continued until chromone 1 was consumed
completely (followed by TLC, approximately 2–3 h). The reaction
mixture was quenched with aqueous solution of 10% NH4Cl,
washed with water, dried (Na2SO4), the solvent was distilled off in
vacuo, and the resulting residue was subjected to column chro-
matography on silica gel using petroleum ether–AcOEt (7:1) as
eluent, slowly increasing the polarity up to 4:1 to give the isolated
products.
4.2. General procedure for the reaction of chromones (1a–1g)
with dimethyl acetonedicarboxylate
To a stirred reaction mixture of chromone 1 (1.0 mmol) and
dimethyl acetonedicarboxylate (0.22 g, 1.1 mmol) in THF (20 mL),
R1
COCH2COOMe
COOMe
R2
R2
R1
O
O
R2
R1
O
O
DBU
THF
COOMe
O
DBU
O
C
MeO
OMe
+
O
O
O
O
COOMe
O
O
O
H
16
1d-g
R1
O
R1
R1
R2
R2
R2
COOMe
COOMe
O
COOMe
O
-H2O
OH
O
O
O
O
O
COOMe
COOMe
O
COOMe
H
H
H
17
18
5d-g
Scheme 4. Plausible reaction mechanism proposed for the formation of compounds 5.

M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
11615
H
OMe
OMe
CO
H
H
O
H
H
O
O
O
CO
H
H
H
H
H
H
H
H
H
H
H
OH
O
O
H
H
CH2COOMe
H
O
H
H
O
OC
H
H
C
O
OCH3
O
O
O
H
H
H
H
H
OMe
CO
OCH3
4c
H
H
O
H
H
H
H
OH
CH2COOMe
O
H
O
C
O
OCH3
O
H
2a
3c
Figure 1. Critical COLOC correlations via 2J and 3J for the structure identification of compounds 2a, 3c, and 4c.
4.2.1. Methyl 7-hydroxy-6-oxo-6H-benzo[c]chromene-8-
carboxylate (2a)
1), 131.0 (C-2), 131.9 (C-3), 138.6 (C-10a), 139.1 (C-9), 149.7 (C-4a),
163.3 (C-7), 163.4 (C-6), 166.0 (8-C]O). Anal. Calcd for C15H9ClO5
(304.68): C, 59.13; H, 2.98%. Found: C, 59.29; H, 3.13%.
0.152 g, 56% yield, white solid, mp 203–205 ꢀC (CH2Cl2–pet.
ether); IR (KBr) nmax: 3444 (br), 1719, 1670, 1624 cmꢁ1 1H NMR:
.
4.2.3. Reaction of chromone (1c) with dimethyl
acetonedicarboxylate
3.98 (s, 3H, 8-OCH3), 7.37 (dd, J¼8.2, 1.2 Hz, 1H, 4-H), 7.39 (ddd,
J¼7.8, 7.4,1.2 Hz,1H, 2-H), 7.56 (ddd, J¼8.2, 7.4, 1.5 Hz,1H, 3-H), 7.59
(d, J¼8.6 Hz, 1H, 10-H), 8.04 (dd, J¼7.8, 1.5 Hz, 1H, 1-H), 8.30 (d,
J¼8.6 Hz, 1H, 9-H), 12.57 (s, 1H, 7-OH). 13C NMR: 52.5 (OCH3), 107.3
(C-6a),111.6 (C-10),116.5 (C-8),117.4 (C-10b),117.8 (C-4),123.9 (C-1),
125.4 (C-2),131.8 (C-3),139.0 (C-9),139.8 (C-10a),151.2 (C-4a),163.3
4.2.3.1. In the presence of 1.3 mmol DBU. The reaction was repeated
as above to give after column chromatography on silica gel using
petroleum ether–AcOEt (7:1) as eluent, slowly increasing the po-
larity up to 4:1, in elution order:
ꢂ
(C-7),164.0 (C-6),166.0 (8-C]O). EIMS m/z (%) 270 (91, Mþ ), 253 (5),
239 (100), 210 (25),182 (15),155 (20),154 (19),139 (5),126 (40). Anal.
Calcd for C15H10O5 (270.24): C, 66.67; H, 3.73%. Found: C, 66.46;
H, 3.60%.
Unreacted 3-bromochromone 0.022 g, 10%.
Methyl
furoate (3c). Yield 0.061 g, 19%, yellow solid, mp 206–208 ꢀC
(CH2Cl2–ether); IR (Nujol) nmax: 3250, 1735, 1715 cmꢁ1 1H NMR:
5-(2-hydroxybenzoyl)-2-(2-methoxy-2-oxoethyl)-3-
.
3.77 (s, 3H, 2-OCH3), 3.89 (s, 3H, 3-OCH3), 4.23 (s, 2H, 2-CH2), 6.98
(ddd, J¼8.1, 7.4, 1.1 Hz, 1H, 50-H), 7.05 (dd, J¼8.5, 1.1 Hz, 1H, 30-H),
7.53 (ddd, J¼8.5, 7.4, 1.6 Hz, 1H, 40-H), 7.60 (s, 1H, 4-H), 8.13 (dd,
J¼8.1, 1.6 Hz,1H, 60-H), 11.82 (s, 1H, OH). 13C NMR: 34.0 (2-CH2), 52.1
(3-OCH3), 52.7 (2-OCH3), 117.8 (C-3), 118.5 (C-10), 118.6 (C-30), 119.3
(C-50), 120.9 (C-4), 131.2 (C-60), 136.6 (C-40), 150.1 (C-5), 158.1 (C-2),
162.7 (3-C]O), 163.3 (C-20), 168.0 (2-C]O), 184.5 (5-C]O). EIMS
4.2.2. Methyl 2-chloro-7-hydroxy-6-oxo-6H-benzo[c]chromene-8-
carboxylate (2b)
0.171 g, 56% yield, white solid, mp 227–229 ꢀC (CH2Cl2–pet.
ether); IR (Nujol) nmax: 3440 (br), 1697, 1668 cmꢁ1. 1H NMR: 4.00 (s,
3H, 8-OCH3), 7.36 (d, J¼8.8, 1H, 4-H), 7.52 (dd, J¼8.8, 2.2 Hz, 1H, 3-
H), 7.57 (d, J¼8.4 Hz, 1H, 10-H), 8.03 (d, J¼2.2 Hz, 1H, 1-H), 8.34 (d,
J¼8.4 Hz, 1H, 9-H), 12.51 (s, 1H, 7-OH). 13C NMR: 52.6 (OCH3), 107.5
(C-6a), 111.8 (C-10), 117.4 (C-8), 118.9 (C-10b), 119.3 (C-4), 123.7 (C-
ꢂ
m/z (%) 318 (40, Mþ ), 286 (80), 259 (25), 254 (40), 244 (45), 226
(50), 216 (15), 213 (75), 199 (20), 186 (18), 171 (22), 158 (22), 131
(20), 121 (100), 120 (55), 109 (30). Anal. Calcd for C16H14O7 (318.28):
C, 60.38; H, 4.43%. Found: C, 60.56; H, 4.48%.
Figure 2. ORTEP of compound 4c.
Figure 3. ORTEP of compound 5d.

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M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
Methyl 1-[5-(2-hydroxybenzoyl)-3-(methoxycarbonyl)-2-furyl]-
7.07 (d, J¼9.3 Hz, 1H, 30-H), 7.47 (dd, J¼9.3, 2.3 Hz, 1H, 40-H), 7.50 (d,
J¼2.3 Hz, 1H, 60-H), 8.44 (s, 2H, 4,6-H), 11.60 (s, 1H, 20-OH), 12.32 (s,
1H, 1-OH). 13C NMR: 53.0 (2ꢃCH3), 116.9 (C-5), 119.4 (10), 120.4 (C-
30), 123.8 (C-50), 127.7 (C-1,3), 131.6 (C-60), 136.5 (C-40), 137.3 (C-4,6),
161.6 (C-20), 164.4 (C-2), 167.2 (1,3-C]O), 197.2 (5-C]O). EIMS m/z
7-oxo-1,1a,7,7a-tetrahydrocyclopropa[b]chromene-1-carboxylate
(4c). Yield 0.097 g, 42%, yellow solid, mp 210–212 ꢀC (CH2Cl2–
ether); IR (Nujol) nmax: 3444,1741,1715,1684 cmꢁ1. 1H NMR: 3.76 (s,
3H, 1-OCH3), 3.99 (s, 3H, 30-OCH3), 3.45 (br d, 1H, J¼6.7 Hz, 7a-H),
5.23 (d, 1H, J¼6.7 Hz, 1a-H), 6.75 (dd, J¼8.4, 1.0 Hz, 1H, 3-H), 6.82
(ddd, J¼8.1, 7.3, 1.0 Hz, 1H, 5-H), 7.01 (dd, J¼8.5, 0.9 Hz, 1H, 300-H),
7.07 (ddd, J¼8.2, 7.1, 0.9 Hz, 1H, 500-H), 7.28 (ddd, J¼8.4, 7.3, 1.7 Hz,
1H, 4-H), 7.29 (s, 1H, 40-H), 7.54 (ddd, J¼8.5, 7.1, 1.7 Hz, 1H, 400-H),
7.60 (dd, J¼8.1, 1.7 Hz, 1H, 6-H), 7.92 (dd, J¼8.2, 1.7 Hz, 1H, 600-H),
11.87 (s, 1H, OH). 13C NMR: 27.3 (C-1), 37.9 (C-7a), 52.4 (OCH3), 53.8
(OCH3), 65.1 (C-1a), 117.0 (C-3), 118.0 (C-100), 118.5 (C-300), 118.7 (C-
30), 119.4 (C-500), 120.3 (C-40), 122.1 (C-6a), 122.5 (C-5), 126.1 (C-6),
131.4 (C-600), 136.3 (C-4), 136.9 (C-400), 151.5 and 151.7 (C-20 and C-
50), 157.4 (C-2a), 161.7 (30-C]O), 163.6 (C-200), 168.8 (1-C]O), 183.2
ꢂ
(%) 364/366 (29, Mþ ), 332/334 (100), 300/302 (30), 288/290 (18),
272/274 (90), 244/246 (30), 205/207 (35), 155/157 (50). Anal. Calcd
for C17H13ClO7 (364.73): C, 55.98; H 3.59%. Found: C, 55.79; H,
3.66%.
4.2.8. Dimethyl 5-(5-chloro-2-hydroxy-4-methyl-benzoyl)-
2-hydroxyisophthalate (5g)
Yield 0.202 g, 52%, white solid, mp 146–149 ꢀC (CH2Cl2–ether);
IR (Nujol) nmax: 3443, 1752, 1690 cmꢁ1. 1H NMR: 2.43 (s, 3H, CH3),
4.00 (s, 6H, 2ꢃCH3), 7.00 (s, 1H, 30-H), 7.49 (s, 1H, 60-H), 8.43 (s, 2H,
4,6-H), 11.65 (s, 1H, 20-OH), 12.32 (s, 1H, 2-OH). 13C NMR: 20.9 (40-
CH3), 53.0 (2ꢃOCH3), 116.8 (C-5),117.7 (10), 120.8 (C-30),124.5 (C-50),
127.9 (C-1,3), 132.0 (C-60), 137.2 (C-4,6), 146.1 (C-40), 161.6 (C-20),
164.3 (C-2), 167.3 (1,3-C]O), 196.9 (5-C]O). EIMS m/z (%) 378/380
ꢂ
(C-7), 183.6 (50-C]O). LC/MS (ESI, 3.5 eV) m/z (%) 463 (100, Mþ þ1),
431 (71), 403 (33). Anal. Calcd for C25H18O9 (462.41): C, 64.94; H,
3.92%. Found: C, 64.78; H, 4.01%.
ꢂ
4.2.3.2. In the presence of 2.0 mmol DBU. The reaction was repeated
as above to give, after column chromatography on silica gel using
petroleum ether–AcOEt (7:1) as eluent, slowly increasing the po-
larity up to 4:1, in elution order: Compound 3c, yield 0.019 g, 6%,
and 4c, yield 0.150 g, 65%.
(45, Mþ ), 346/348 (100), 314/316 (40), 302/304 (30), 286/288 (73),
258/260 (30), 205 (20), 169/171 (40). Anal. Calcd for C18H15ClO7
(378.76): C, 57.08; H 3.99%. Found: C, 56.89; H, 4.03%.
References and notes
4.2.4. Reaction of 3c with dimethyl acetonedicarboxylate
1. (a) Dewick, P. M. In The Flavonoids: Advances in Research Since 1986; Harborne,
J. B., Ed.; Chapman & Hall: New York, NY, 1994; pp 117–238; (b) Gill, M. In The
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1998; Vol. 439.
2. (a) Korkina, G. L.; Afanas’ev, I. B. In Advances in Pharmacology; Sies, H., Ed.;
Academic: San Diego, 1997; Vol. 38, pp 151–163; (b) Comprehensive Medicinal
Chemistry; Hansch, C., Sammes, P. G., Taylor, J. B., Eds.; Pergamon: New York, NY,
1990; Vol. 6.
To a stirred reaction mixture of the furoate 3c (0.032 g, 0.1 mmol)
and 3-bromochromone (0.025 g, 0.11 mmol) in THF (3 mL), DBU
(0.020 mL, 0.013 mmol) was added via a syringe at room tempera-
ture. Stirring was continued until 3c was consumed completely
(followed by TLC, approximately 2–3 h). The reaction mixture was
quenched with aqueous solution of 10% NH4Cl, washed with water,
dried (Na2SO4), the solvent was distilled off in vacuo, and the
resulting residue was subjected to column chromatography on silica
gel using petroleum ether–AcOEt (7:1) as eluent, slowly increasing
the polarity up to 4:1 to give 4c, yield 0.036 g, 78%.
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4.2.5. Dimethyl 5-(2-hydroxybenzoyl)-2-hydroxyisophthalate (5d)
Yield 0.243 g, 65%, white solid, mp 81–83 ꢀC (CH2Cl2–ether); IR
(Nujol) nmax: 3443, 1701, 1676 cmꢁ1. 1H NMR: 3.99 (s, 6H, 2ꢃCH3),
6.94 (ddd, J¼8.1, 7.1,1.2 Hz,1H, 50-H), 7.10 (dd, J¼8.6,1.2 Hz,1H, 30-H),
7.55 (dd, J¼8.1,1.7 Hz,1H, 60-H), 7.55 (ddd, J¼8.6, 7.1,1.7 Hz,1H, 40-H),
8.45 (s, 2H, 4,6-H), 11.75 (s, 1H, 20-OH),12.29 (s, 1H, 2-OH). 13C NMR:
52.8 (2ꢃCH3),116.7 (C-5),118.7 (C-30),118.8 (C-10),119.0 (C-50),128.3
(C-1,3), 132.7 (C-60), 136.5 (C-40), 137.4 (C-4,6), 163.1 (C-20), 164.1
9. Vanden Eynde, J. J.; Hecq, N.; Kataeva, O.; Kappe, C. O. Tetrahedron 2001, 57,
1785–1791.
ꢂ
(C-2), 167.3 (1,3-C]O), 198.1 (5-C]O). EIMS m/z (%) 330 (69, Mþ ),
10. Fitton, A. O.; Houghton, P. G.; Suschitzky, H. Synthesis 1979, 337–339.
11. Cremmins, P. J.; Hayes, R.; Wallace, T. W. Tetrahedron 1991, 47, 9431–9438.
298 (100), 267 (37), 254 (45), 238 (83), 210 (42),121 (60). Anal. Calcd
for C17H14O7 (330.28): C, 61.82; H, 4.27%. Found: C, 62.09; H, 4.32%.
´
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4.2.6. Dimethyl 2-hydroxy-5-(2-hydroxy-5-methyl-benzoyl)-
isophthalate (5e)
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2001, 9, 629–636.
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1108–1117.
17. (a) Ghosh, C. K.; Khan, S. Synthesis 1981, 903; (b) Bandyopadhyay, C.; Sur, K. R.;
Patra, R. J. Chem. Res., Synop. 1998, 802–803.
18. (a) Langer, P.; Saleh, N. N. R.; Freifeld, I. Chem. Commun. 2002, 168–169; (b)
Appel, B.; Saleh, N. N. R.; Langer, P. Chem.dEur. J. 2006, 12, 1221–1236; (c) Ullah,
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Appel, B.; Langer, P. Tetrahedron 2006, 62, 7674–7686; (c) Lubbe, M.; Appel, B.;
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21. (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, 2897–2905; (b) Liou, J.-P.; Chang, C.-W.;
51% yield, white solid, mp 158–159 ꢀC (CH2Cl2–pet. ether); IR
(Nujol) nmax: 3443, 1716, 1685 cmꢁ1. 1H NMR: 2.27 (s, 3H, 50-CH3),
3.98 (s, 6H, 2ꢃCH3), 6.99 (d, J¼8.5 Hz, 1H, 30-H), 7.30 (d, J¼1.0 Hz,
1H, 60-H), 7.35 (dd, J¼8.5, 1.0 Hz, 1H, 40-H), 8.44 (s, 2H, 4,6-H), 11.55
(s, 1H, OH), 12.27 (s, 1H, OH). 13C NMR: 20.5 (CH3), 52.8 (2ꢃCH3),
116.6 (C-5), 118.4 (C-10,30), 128.2 (C-1,3), 128.5 (C-50), 132.4 (C-60),
137.3 (C-4,6), 137.6 (C-40), 161.0 (C-20), 164.0 (C-2), 167.4 (1,3-C]O),
ꢂ
198.1 (5-C]O). EIMS m/z (%) 344 (60, Mþ ), 312 (100), 280 (30), 268
(25), 252 (91), 224 (25), 205 (15), 134 (35). Anal. Calcd for C18H16O7
(344.32): C, 62.79; H, 4.68%. Found: C, 63.01; H, 4.71%.
4.2.7. Dimethyl 2-hydroxy-5-(5-chloro-2-hydroxy-benzoyl)-
isophthalate (5f)
Yield 0.243 g, 65%, white solid, mp 156–158 ꢀC (CH2Cl2–ether);
IR (Nujol) nmax: 3443,1718,1685 cmꢁ1. 1H NMR: 4.00 (s, 6H, 2ꢃCH3),

M.A. Terzidis et al. / Tetrahedron 64 (2008) 11611–11617
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charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax (int.
code): þ44 1223 336 033, e-mail: deposit@ccdc.cam.ac.uk).