Synthesis of 2,3,6,8-tetrasubstituted chromone scaffolds

Article abstract of DOI:10.1021/jo061008f

A useful and efficient synthetic strategy to 2,3,6,8-tetrasubstituted chromone derivatives has been developed. 2-Aryl/styryl-8-bromo-6-chloro-3- hydroxychromone derivatives were synthesized and used as scaffolds by introducing a variety of substituents in

Full text of DOI:10.1021/jo061008f

Synthesis of 2,3,6,8-Tetrasubstituted Chromone Scaffolds
Kristian Dahle´n,† Erik A. A. Walle´n,†,‡ Morten Grøtli,† and Kristina Luthman†,*
Department of Chemistry, Medicinal Chemistry, Go¨teborg UniVersity, SE-412 96 Go¨teborg, Sweden, and
Department of Pharmaceutical Chemistry, UniVersity of Kuopio, FI-70211 Kuopio, Finland
luthman@chem.gu.se
ReceiVed May 16, 2006
A useful and efficient synthetic strategy to 2,3,6,8-tetrasubstituted chromone derivatives has been
developed. 2-Aryl/styryl-8-bromo-6-chloro-3-hydroxychromone derivatives were synthesized and used
as scaffolds by introducing a variety of substituents in the 3-, 6-, and 8-positions using palladium-mediated
reactions. Excellent regioselectivity in all positions could be obtained by performing reactions in the
8-position first, in which Stille, Heck, Suzuki, and Sonogashira reactions gave good to excellent yields
of product (63-98%). Stille and Heck reactions in the 6-position also gave the desired products in good
yields (64-86%). The hydroxy group in the 3-position was activated as a triflate and used in productive
Stille reactions (63-94%). This hydroxyl group was also used in O-alkylation reactions with different
functionalized alkyl bromides (57-88%). The flavonoids, which are based on the chromone structure,
and other related ring systems, have several interesting biological activities. The chromones are also
interesting structural scaffolds, and they have for example been designed to be used as mimetics of short
peptides. The versatile applicability of chromone derivatives and especially their potential use in drug
discovery implicates the importance of access to efficient synthetic routes to such compounds.
Introduction
The chromones are also interesting as structural scaffolds and
have been assigned as privileged structures for drug develop-
ment.15 Chromone derivatives, with different functionalized
substituents, have for example been designed to be used as
mimetics of short peptides.16 Furthermore, the flavonols (3-
hydroxy-2-phenyl-chromones) have been demonstrated to have
excellent fluorescent properties,17-21 which could be exploited
The flavonoids represent one of the largest groups of natural
products known; several thousand derivatives have been identi-
fied.1 The flavonoids are based on the flavone (2-phenyl-4-
chromone) and related ring systems and constitute an important
class of widely distributed plant secondary metabolites. In
addition to the various functions of flavonoids in plants, their
widespread distribution in nature, their structural variability, their
relatively low toxicity, and their antioxidant activities have
increased the interest in flavonoids as beneficial for human
health.2 Several therapeutically interesting biological activities
of certain flavonoids have been reported including anticancer,3-8
anti-HIV,9-11 and antioxidant12-14 properties.
(3) Birt, D. F.; Hendrich, S.; Wang, W. Pharmacol. Ther. 2001, 90, 157-
177.
(4) Lo´pez-La´zaro, M. Curr. Med. Chem - Anti-Cancer Agents 2002, 2,
691-714.
(5) Pouget, C.; Lauthier, F.; Simon, A.; Fagnere, C.; Basly, J.-P.; Delage,
C.; Chulia, A.-J. Bioorg. Med. Chem. Lett. 2001, 11, 3095-3097.
(6) Zheng, X.; Meng, W. D.; Xu, Y. Y.; Cao, J. G.; Qing, F. L. Bioorg.
Med. Chem. Lett. 2003, 13, 881-884.
(7) Gobbi, S.; Rampa, A.; Bisi, A.; Belluti, F.; Piazzi, L.; Valenti, P.;
Caputo, A.; Zampiron, A.; Carrara, M. J. Med. Chem. 2003, 46, 3662-
3669.
* Address correspondence to Department of Chemistry - Medicinal Chemistry,
Go¨teborg University, SE-412 96 Go¨teborg, Sweden. Telephone: +46-31-772
2894. Fax: +46-31-772 3840. E-mail: luthman@chem.gu.se.
† Go¨teborg University.
(8) Atassi, G.; Briet, P.; Berthelon, J. J.; Collonges, F. Eur. J. Med. Chem.
1985, 20, 393-402.
‡ University of Kuopio.
(9) Yu, D.; Chen, C. H.; Brossi, A.; Lee, K. H. J. Med. Chem. 2004, 47,
4072-4082.
(1) Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481-
504.
(10) Hu, C.; Chen, K.; Shi, Q.; Kilkuskie, R. E.; Chen, Y.; Lee, K. H.
J. Nat. Prod. 1994, 57, 42-51.
(2) Havsteen, B. H. Pharmacol. Ther. 2002, 96, 67-202.
10.1021/jo061008f CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/01/2006
J. Org. Chem. 2006, 71, 6863-6871
6863

Dahle´n et al.
SCHEME 1. Synthesis of 3,6,8-Trisubstituted Flavonesa
FIGURE 1. Retrosynthetic analysis of 2,3,6,8-tetrasubstituted chromones.
in various applications, e.g. as probes to study lipid membranes
and proteins.22-24 The versatile biological applicability of
chromone derivatives and their potential use in drug discovery
implicate the importance of access to efficient synthetic routes
to well designed substituted chromone derivatives.
The focus of the present study is the synthesis of 2,3,6,8-
tetrasubstituted chromones (Figure 1). A literature search
revealed that only a few chromone derivatives with this
substitution pattern have been reported previously.25-29 In
addition, the published compounds were cyclized to the
chromone after the substituents had been introduced, and only
undemanding substituents (e.g. Me, COCH3 and OH) had been
used.
The aim of the present study was therefore to develop a
general synthetic route to 2,3,6,8-tetrasubstituted chromones with
functionalized substituents using a scaffold approach. The study
was started with the development of a scaffold for 3,6,8-
trisubstituted flavones; however, other aryl groups than phenyl
can also be introduced in the 2-position. As the substituents
are connected to the ring system through carbon-carbon bonds
and the substituents will contain various functional groups, the
most effective and versatile chemistry was believed to be
accomplished using palladium-mediated reactions. Some initial
results were published recently by our group, where the general
synthetic strategy was also presented.30
a Reagents and conditions: (i) (a) Benzoyl chloride, pyridine, rt, 1 h;
(b) KOH, pyridine, 50 °C, 2 h; (ii) HCl, HOAc, reflux, 14 h; (iii) (a) ICl,
DMF; or (b) Br2, dioxane/DMF; (iv) (a) NIS or NBS, CHCl3 or DMF; or
(b) NIS or NBS, AIBN, benzene; or (c) NaH, LDA or K2CO3,
BrCH2CH2NPhth, THF or acetone. Phth ) Phthalimide.
Results and Discussion
To introduce substituents in the 3-, 6-, and 8-positions of the
flavone ring system, palladium-mediated chemistry was used.
For such reactions to proceed, either halogens or triflates at these
positions are needed.
Halogens at the 6- and 8-positions can easily be introduced
in the starting material before the cyclization of the chromone
ring (Scheme 1). The chosen scaffold approach required a
working strategy for regioselectivity. Therefore, the difference
in reactivity between the 6- and 8-positions was first studied.
A Heck reaction with methyl acrylate on 6,8-dibromoflavone
(5) gave mixtures of products, as both 6- and 8-monosubstituted
and 6,8-disubstituted flavones were formed. Thus, the difference
in reactivity at the 6- and 8-positions in flavones was not
sufficient to provide regioselectivity; instead, the use of two
different halogens (e.g. Br and Cl) was needed.
(11) Ungwitayatorn, J.; Samee, W.; Pimthon, J. J. Mol. Struct. 2004,
689, 99-106.
(12) Burda, S.; Oleszek, W. J. Agric. Food Chem 2001, 49, 2774-2779.
(13) Rackova, L.; Firakova, S.; Kostalova, D.; Stefek, M.; Sturdik, E.;
Majekova, M. Bioorg. Med. Chem. 2005, 13, 6477-6484.
(14) Soobrattee, M. A.; Neergheen, V. S.; Luximon-Ramma, A.; Aruoma,
O. I.; Bahorun, T. Mutat. Res. 2005, 579, 200-213.
(15) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893-930.
(16) Dahle´n, K.; Grøtli, M.; Luthman, K. Understanding Biology Using
Peptides; Blondelle, S., Ed.; American Peptide Society: San Diego, 2006;
pp 677-678.
Several strategies to introduce halogens at the 3-position of
flavones are available in the literature.31-33 However, in our
hands these reactions proved to be difficult. Reactions of 4 with
ICl in refluxing DMF to obtain 7a or with Br2 in dioxane/DMF
to afford 7b did not result in any product formation (Scheme
1). We also failed to introduce iodide or bromide in the
3-position of flavone 6, as reactions with NIS or NBS,
respectively, in different solvents did not give any of the desired
products. Alternatively, the 3-position has also been directly
alkylated.34,35 Alkylation of 6 with different alkyl bromides (e.g.
(17) Sengupta, P. K.; Kasha, M. Chem. Phys. Lett. 1979, 68, 382-385.
(18) Swinney, T. C.; Kelley, D. F. J. Chem. Phys. 1993, 99, 211-221.
(19) Mcmorrow, D.; Kasha, M. J. Phys. Chem. 1984, 88, 2235-2243.
(20) Klymchenko, A. S.; Demchenko, A. P. J. Am. Chem. Soc. 2002,
124, 12372-12379.
(21) Klymchenko, A. S.; Mely, Y. Tetrahedron Lett. 2004, 45, 8391-
8394.
(22) Klymchenko, A. S.; Avilov, S. V.; Demchenko, A. P. Anal. Biochem.
2004, 329, 43-57.
(23) Bondar, O. P.; Pivovarenko, V. G.; Rowe, E. S. Biochim. Biophys.
Acta Biomembr. 1998, 1369, 119-130.
(24) Klymchenko, A. S.; Duportail, G.; Ozturk, T.; Pivovarenko, V. G.;
Mely, Y.; Demchenko, A. P. Chem. Biol. 2002, 9, 1199-1208.
(25) Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Smith, D.
A. Chem. Commun. 1983, 1098-1099.
(26) Flynn, D. G.; Robertson, A. J. Chem. Soc. 1936, 215-217.
(27) Fillol, L.; Martinezutrilla, R.; Miranda, M. A.; Morera, I. M.
Heterocycles 1989, 29, 511-520.
(28) Da Re, P.; Verlicchi, L. Arch. Pharm. 1963, 296, 714-717.
(29) Dare, P.; Cimatori. L Experientia 1962, 18, 67-68
(30) Dahle´n, K.; Grøtli, M.; Luthman, K. Synlett 2006, 897-900.
(31) Bhadange, R. E.; Doshi, A. G.; Raut, A. W. Asian J. Chem. 2002,
14, 509-511.
(32) Mazumdar, A. K. D.; Karmakar, P. K.; Rahman, M.; Saha, G. C.;
Rangachari, K.; Banerji, K. D. J. Indian Chem. Soc. 1992, 69, 207-209.
(33) Sosnovskikh, V. Y. Russ. Chem. ReV. 2003, 72, 489-516.
(34) Zheng, X.; Cao, J. G.; Meng, W. D.; Qing, F. L. Bioorg. Med. Chem.
Lett. 2003, 13, 3423-3427.
6864 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2,3,6,8-Tetrasubstituted Chromones
TABLE 1. O-Alkylation Reactions in the 3-Position of the
Flavonols 14-16 and 19
SCHEME 2. Synthesis of
8-Bromo-6-chloro-3-hydroxy-chromonesa
compound
R2
R3
yielda (%)
20
21
22
23
24
25
Ph
(CH2)3NPhth
(CH2)3NPhth
(CH2)3NPhth
(CH2)2NPhth
(CH2)2NPhth
CH2CO2Et
87b
88
86
71
57
81
4-MeO-Ph
4-CF3-Ph
Ph
CHdCHPh
Ph
a Isolated yields. b For synthesis of 20, see ref 30. Phth ) phthalimide.
a Reagents and conditions: (i) Aldehyde, KOH, EtOH, 50 °CfRT, 14
h; (ii) NaOH, H2O2, MeOH/THF, 0 °CfRT, overnight.
ate alkyl bromide in the presence of K2CO3 in DMF to obtain
20-23 and 25 in good yields (71-88%). In the same reaction,
compound 19 gave 24 which was isolated in a modest yield
(57%). This was most likely a result of the difficulties observed
in the separation of unreacted N-(2-bromoethyl)-phthalimide
from the product by flash chromatography.
N-(2-bromoethyl)phthalimide) in the present of a base (NaH,
LDA, or K2CO3) did not, however, result in any product
formation.
Due to problems in introducing halogens or performing
alkylation reactions in position 3, another synthetic strategy
starting from the flavonol (3-hydroxyflavone) was adopted. The
3-hydroxyl group can when needed be transformed to a triflate
which is also a good leaving group in Pd-mediated reactions.36-39
In addition, the 3-hydroxyl group can be utilized in O-alkylation
reactions which is an easy alternative to palladium-mediated
chemistry if an ether link can be tolerated in the target
compound. Variations in the substitution pattern in the 2-position
to obtain 2,3,6,8-tetrasubstituted chromones can be accomplished
by introducing different aryl/styryl groups before cyclization
of the chromone ring.
The 2-aryl/styryl-8-bromo-6-chloro-3-hydroxy-chromones were
synthesized from 3-bromo-5-chloro-2-hydroxy-acetophenone (2)
and the appropriate aldehyde using KOH in EtOH, followed
by cyclization of the intermediate chalcone using NaOH and
H2O2 in THF/MeOH (Scheme 2).40-43 Both reaction steps gave
generally good yields. In the formation of the chalcone,
p-methoxybenzaldehyde showed the lowest reactivity, whereas
the cyclization of the chalcone from p-trifluoromethylbenzal-
dehyde gave the lowest yield of flavonol (41%). Thus, electron
rich aryl groups decrease the reactivity in the first step, and
electron deficient aryl groups decrease the reactivity in the
second step. The use of cinnamic aldehyde afforded 19 also in
good yield (66%).
Palladium-Mediated Reactions. Triflates and bromides are
known to have similar reactivity in Pd-mediated reactions. To
see whether this is true also for the 3- and 8-positions in
8-bromo-6-chloro-3-trifluoromethylsulfonyl-flavone, a Stille
cross-coupling reaction on 26 using allyltributyltin was per-
formed. The reaction resulted in a mixture of 3- and 8-mono-
substituted and 3,8-disubstituted products which showed that
there was no selectivity between a 3-triflate and an 8-bromo
substituent in the flavone ring system. However, it showed
clearly that the 3-triflate is useful in Pd-coupling reactions. Thus,
the synthetic strategy starting from 2-aryl/styryl-8-bromo-6-
chloro-3-hydroxy-chromone allows the introduction of a triflate
group at the 3-position when needed. Although the 8-position
has to be reacted first, this allows flexibility regarding the order
that the substituents at the 3- and 6-positions are introduced.
However, the free 3-hydroxyl group could cause solubility
problems in typical organic solvents and/or difficulties in flash
chromatographic purifications. Acetylation of the hydroxyl
group circumvented these problems, e.g. 15 was acetylated to
27 using acetyl chloride and NEt3 in CH2Cl2 in good yield
(>99%).
Stille and Heck reactions were used for the introduction of
substituents in the 3-, 6-, and 8-positions, whereas Sonogashira
and Suzuki reactions were only tested in the 8-position.44-47 In
our initial study we used the Stille cross-coupling with allyl
O-Alkylation in the 3-Position. O-Alkylation in the 3-posi-
tion was used to introduce different functionalized substituents
(Table 1). Compounds 14-16 were alkylated with the appropri-
(35) Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Varma, R.
S. J. Chem. Soc., Perkin Trans. 1 1985, 799-808.
(36) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 5478-
5486.
(37) Ritter, K. Synthesis 1993, 735-762.
(38) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
3066.
(39) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442-4489.
(44) de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. 1994, 33, 2379-
(40) Davis, F. A.; Chen, B. C. J. Org. Chem. 1993, 58, 1751-1753.
(41) Ali, S. M.; Ilyas, M. J. Org. Chem. 1986, 51, 5415-5417.
(42) Utale, P. S.; Ranghuwanshi, P. B.; Doshi, A. G. Asian J. Chem.
1999, 11, 644-646.
2411.
(45) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43,
4704-4734.
(46) Hesse, S.; Kirsch, G. Tetrahedron Lett. 2003, 44, 97-99.
(47) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-
4211.
(43) Bennett, C. J.; Caldwell, S. T.; McPhail, D. B.; Morrice, P. C.;
Duthie, G. G.; Hartley, R. C. Bioorg. Med. Chem. 2004, 12, 2079-2098.
J. Org. Chem, Vol. 71, No. 18, 2006 6865

Dahle´n et al.
TABLE 2. Palladium-Mediated Reactions in the 8-Position
tributyltin and the Heck reaction with methyl acrylate, and it
was shown that it is possible to obtain the desired products in
good yield and with excellent regioselectivity.30
The Stille reaction was used to introduce either an allyl or
benzyl substituent. The allyl substituent can easily be function-
alized using a variety of reactions, e.g. hydroxylation followed
by oxidation to an aldehyde or a carboxylic acid. The Heck
reaction was used to introduce an R,â-unsaturated ester func-
tionality which can also be modified by further reactions.
The Sonogashira reaction was used to introduce either a TMS-
acetylene or a Boc-protected propargylamine. After removing
the TMS protecting group, the triple bond can be converted to
other functionalities e.g. via oxidation or via reduction to
ethylene. A terminal triple bond can also be used in further
Sonogashira reactions, in reactions with azides,48 or in reaction
with primary amines to give imines.49 The Suzuki reaction was
used to introduce a sterically demanding naphthyl group in the
8-position.
Reactions at Position 8. Stille Cross-Coupling Reactions.
The Stille cross-coupling reaction was first performed on 14
and 20 using allylSnBu3 or benzylSnBu3 and Pd(PPh3)4 with
thermal heating, to provide 28 and 37 in good yields (89% and
63%, respectively) as was reported earlier.30 However, when
reacting compounds with other groups than phenyl at the
2-position, only fast heating to high temperatures in a sealed
vessel using a microwave cavity gave the desired high yields
and reproducibility. Therefore, microwave heating at 150-160
°C in DMF was preferable for these reactions.50 Stille cross-
coupling of 14-18 in a microwave cavity gave products 29-
33 in good to excellent yields (64-98%) (Table 2). The free
3-hydroxy groups caused some difficulties in the purification,
as repeated flash chromatography was needed. However, when
using the 3-acetoxy derivative 27, the product was easily purified
by flash chromatography to give 45 in good yield (78%). Stille
reactions on substrates with other substituents present in the
3-position were also investigated, e.g. coupling of 20-22 with
benzylSnBu3 or allylSnBu3 gave the corresponding products (37-
40) in high yields (63-95%).
Heck Reactions. Heck reactions of 14 with methyl acrylate,
Pd(OAc)2, P(o-tolyl)3, and NEt3 in DMF gave 34 in 80% yield
(Table 2). The same reaction but with 20 as starting material
was also productive affording 41 in 87% yield.
Sonogashira Reactions. The Sonogashira reaction was run
in a microwave cavity at 120 °C using 14, TMS-acetylene,
PdCl2(PPh3)2, NEt3, and CuI in THF to afford 35 in 71% yield
(Table 2). Using 20 as starting material with the same conditions
provided 42 (91%). Using 25 as starting material in a Sono-
gashira coupling with Boc-protected propargylamine gave 44
(83%).
Suzuki Reactions. Suzuki reactions were run using 14,
2-naphthylboronic acid, Pd(PPh3)4, and Cs2CO3 in DMF heated
in a microwave cavity to obtain 36 (79%) (Table 2). However,
the crude alcohol was first transferred to its corresponding acetyl
ester to simplify the purification. The pure product was directly
hydrolyzed to afford 36. The same reaction conditions were used
with 20 as starting material to give 43 (86%).
yieldb
(%)
compd methoda
R2
R3
R8
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
Ac
Ad
Ad
Ad
Ad
Ad
B
Ph
Ph
H
H
H
H
H
H
H
H
H
allyl
Bn
Bn
Bn
Bn
Bn
89
64
77
86
98
89
80
71
79e
63
81
95
91
87
91
86
83
78
4-MeO-Ph
4-CF3-Ph
2-thienyl
3-thienyl
Ph
CHdCHCO2Me
C≡C-TMS
C
D
Ph
Ph
Ph
2-naphthyl
Ac
Ad
Ad
Ad
B
(CH2)3NPhth Bn
4-MeO-Ph (CH2)3NPhth Bn
4-CF3-Ph
(CH2)3NPhth Bn
(CH2)3NPhth allyl
(CH2)3NPhth CHdCHCO2Me
(CH2)3NPhth C≡C-TMS
(CH2)3NPhth 2-naphthyl
Ph
Ph
Ph
Ph
Ph
C
D
C
CH2CO2Et
C≡CCH2NHBoc
Ad
4-MeO-Ph COMe
Bn
a A: AllylSnBu3 or BnSnBu3, Pd(PPh3)4, DMF; B: methyl acrylate,
Pd(OAc)2, P(o-tol)3, NEt3, DMF, 160 °C, 30 min, microwave heating; C:
HCtC-TMS or HCtCCH2NHBoc, PdCl2(PPh3)2, NEt3, CuI, THF, 120
°C, 30 min, microwave heating; D: 2-Naphthylboronic acid, Pd(PPh3)4,
Cs2CO3, DMF, 150 °C, 30 min, microwave heating. b Isolated yields.
c Thermal heating. d Microwave heating. e To overcome difficulties in the
purification the crude product was acetylated. After the purification the
product was deacetylated using NaOMe in MeOH.
The results show that different Pd-mediated reactions can be
used to successfully introduce a variety of substituents in the
8-position with excellent regioselectivity using standard proto-
cols. No differences in reactivity were observed between the
different chromone derivatives used, indicating that the 2-aryl
substituents do not influence the Pd-reactions in the 8-position.
Reactions at Position 3. Stille Cross-Couplings. The use
of aryl triflates in Pd-chemistry has been well established.38,45,46
Triflates of 28 and 30-33 were synthesized in moderate to good
yield (45-77%) using triflic anhydride and NEt3 or pyridine in
CH2Cl2. The triflates were used in Stille couplings with
allylSnBu3 or benzylSnBu3 and Pd(PPh3)4 in a microwave cavity
in high yields (63-94%). This result indicates that the electron-
withdrawing or -donating properties in the 2-aryl ring do not
influence the reactivity of the triflate group in Stille reactions
(Table 3).
Heck Reactions. Heck reactions were attempted using the
same conditions as for the reactions in the 8-position; however,
only trace amounts of product were observed in reactions at
the 3-position. Using standard protocols did also result in trace
amounts of product.51,52 To improve the result, different reaction
conditions were tested using a range of Pd-catalysts [Pd(OAc)2,
PdCl2(PPh3)2, Pd(PPh3)4], ligands [PPh3, P(o-tolyl)3, dppp],
additives [LiCl, Tl2CO3], bases [NEt3, Cs2CO3], solvents [DMF,
dioxane], and reaction temperatures [80 °C, 160 °C, 180 °C].
Unfortunately, changing the reaction conditions did not improve
(48) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216.
(49) Chekulaeva, I. A.; Kondrat′eva, L. V. Russ. Chem. ReV. 1965, 34,
1583-1606.
(50) The previously reported syntheses of 28 and 37 were not repeated
with microwave heating due to previously satisfying yields using thermal
heating.
(51) Kamino, T.; Kuramochi, K.; Kobayashi, S. Tetrahedron Lett. 2003,
44, 7349-7351.
(52) Haaseheld, M.; Hatzis, M.; Mann, J. J. Chem Soc. Perkin Trans. 1
1993, 2907-2911
6866 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2,3,6,8-Tetrasubstituted Chromones
TABLE 3. Palladium-Mediated Reactions in the 3-Position
37 or 45 gave the desired products 54 and 55 (86 and 64%,
respectively).54
It is possible to change the phthalimido protecting group in
the substituent in position 3 of 20 to a Boc-group to provide 52
and thereafter run a Pd-coupling reaction in position 6.55 A Heck
reaction of 52 using methyl acrylate, Pd2dba3, [P(tert-Bu)3H]-
BF4, and NEt3 in dioxane gave 56 in 85% yield. A Boc-group
can in many instances, e.g. in solid-phase peptide synthesis, be
preferable to a phthalimido protecting group.
A Heck reaction was also performed on 51 using methyl
acrylate, Pd2dba3, [P(tert-Bu)3H]BF4, and NEt3 in dioxane in a
microwave cavity to afford 57 in 76% yield. This product
verifies that three different substituents could be introduced
regioselectively in high yield (57 was formed in 51% yield from
17).
compd
R2
R3
R8
yielda (%)
46
47
48
49
50
51
Ph
allyl
allyl
allyl
allyl
allyl
Bn
allyl
Bn
Bn
Bn
Bn
Bn
72
63
70
78
94
69
4-MeO-Ph
4-CF3-Ph
2-Thienyl
3-Thienyl
2-Thienyl
a Isolated yields using the triflates as starting material.
Conclusions
TABLE 4. Palladium-Mediated Reactions in the 6-Position
In the present study a useful general synthetic strategy for
2,3,6,8-tetrasubstituted chromones was developed starting from
2-aryl/styryl-8-bromo-6-chloro-3-hydroxychromone. This scaf-
fold approach allows introduction of different substituents in
the 3-, 6-, and 8-positions using palladium-mediated reactions.
These reactions can without difficulty be performed regiose-
lectively. The 2-substituent consisted of different aryls (phenyl,
p-methoxyphenyl, p-trifluoromethylphenyl, 2-thienyl, 3-thienyl)
and styryl which were introduced before the cyclization of the
flavonol ring. The results show that the choice of aryl/styryl
does not affect the reactivity at the other positions of the
chromone ring system. In general, the palladium-mediated
reactions gave high yields at all positions. Fast heating to high
temperatures in a sealed vessel in a microwave cavity was found
to be a more effective form of heating as compared to traditional
thermal heating as it at all times gave higher yields of products.
The 8-position was reacted through different palladium-
mediated reactions, including Stille, Heck, Sonogashira, and
Suzuki reactions, all affording high yields of products. Substit-
uents could thereafter be introduced either in the 3- or 6-position.
If the 6-position was reacted before the 3-position, the 3-hy-
droxyl group was preferably acetylated to ease the purification
of the intermediates. The 3-hydroxyl group was activated by
formation of the corresponding triflate and reacted in Stille and
Heck reactions using the same conditions as for the 8-position.
Surprisingly, the Heck reaction failed to afford the desired
products; this exception in the series of otherwise successful
palladium-mediated reactions could not be fully explained. Also
the 6-position was reacted in Stille and Heck reactions, providing
the desired products in high yields. The reaction conditions were
different from those used in the 3- and 8-positions, due to the
lower reactivity of aryl chlorides compared to aryl bromides or
triflates.
yieldb
(%)
compd methoda
R2
R3
R6
53
54
55
56
57
A
B
B
B
B
Ph
Ph
O(CH2)3NPhth
O(CH2)3NPhth
allyl
77
86
64
85
76
CHdCHCO2Me
CHdCHCO2Me
4-MeO-Ph OAc
Ph
O(CH2)3NHBoc CHdCHCO2Me
Bn CHdCHCO2Me
2-thienyl
a A: AllylSnBu3, Pd2dba3, P(t-Bu)3, dioxane, 80 °C, 14 h; B: methyl
acrylate, Pd2dba3, [P(t-Bu)3H]BF4, NEt3, dioxane, 160 °C, 30 min,
microwave heating. b Isolated yields. Phth ) phthalimide.
the result. The major side products were found to be the 3-H
derivative formed by reduction of the triflate and/or the 3-OH
derivative formed by hydrolysis of the triflate.
Reactions at Position 6. The reactivity in the 6-position in
the flavone system using Stille and Heck reactions was shown
in our previous study.30 Here the same reactions were used to
react the different chromone derivatives to investigate if there
was a difference in reactivity depending on substituents in
positions 2 or 3. We found that to get the Pd-mediated reactions
to proceed in the 6-position, a more electron-rich and sterically
hindered phosphine ligand, such as P(tert-Bu)3, was necessary.47
Stille Cross-Couplings. A Stille cross-coupling of 37 using
allylSnBu3, Pd2dba3, and P(tert-Bu)3 in dioxane at 80 °C
provided 53 in good yield (77%) (Table 4).
Heck Reactions.53 Also a Heck reaction using methyl
acrylate, Pd2dba3, [P(tert-Bu)3H]BF4, and NEt3 in dioxane on
The palladium-mediated reactions were used to introduce a
variety of substituents. Various combinations were also tried
(53) The phosphine was added as the [P(tert-Bu)3H]BF4 salt which is
more stable and easier to handle than the phosphine itself. This phosphine
is activated when base is added.
(54) Compound 55 could easily be deacetylated using NaOMe in MeOH
to obtain 58 in excellent yield (>98%).
(55) Deprotection of the phthalimide group in 37 was performed using
ethylenediamine in refluxing ethanol for 5 h. The primary amine was not
isolated but instead reacted with di-tert-butyl dicarbonate in MeOH/THF
at reflux for 14 h to obtain the Boc-protected amine 52 (87%).
J. Org. Chem, Vol. 71, No. 18, 2006 6867

Dahle´n et al.
General Procedure for the Synthesis of Chalcones 8-13. KOH
(2.9 equiv) was added to a suspension of 2 (1.0 equiv) and the
appropriate aldehyde (1.05 equiv) in EtOH (6 mL/mmol acetophe-
none). The mixture was stirred at 50 °C for 3 h and then at room
temperature overnight. The reaction mixture was poured into water
and acidified with aqueous HCl (1 M). The product crystallized
and was filtered off. The chalcones were used in the next step
without any other characterization than 1H and 13C NMR spectros-
copy. Spectroscopic and analytical data for some representative
examples of 8-13 follow.
out, since different biological applications have different
requirements. The use of chromone derivatives as peptide
mimetics might require an amino group in one position and a
carboxylic acid group at another. As the flavonols are also
studied as fluorescent probes, substituents with conjugated
unsaturated moieties may be needed to optimize the spectral
properties of the compounds, or substituents with different
functional groups may be needed to attach the fluorescent
flavonol derivative to other compounds.
Flavone and other chromone derivatives have high potential
in drug discovery. Synthesis of large compound libraries is a
general trend in a modern drug discovery process. Furthermore,
computer-aided drug design can be used to perform virtual
screening before the compounds are synthesized. Both meth-
odologies require rapid synthesis of the compounds preferably
from a limited number of starting materials. The presented
scaffold approach in combination with palladium-mediated
chemistry meets these requirements.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-3-phenyl-2-propen-1-
one (8). Benzaldehyde (0.45 g, 4.2 mmol) gave 1.3 g (96%) of 8
1
recrystallized from EtOH. Mp 128-129 °C. H NMR δ 7.47-
7.50 (m, 3H), 7.57 (d, J ) 15.4 Hz, 1H), 7.70-7.72 (m, 2H), 7.78
(d, J ) 2.2 Hz, 1H), 7.88 (d, J ) 2.2 Hz, 1H), 8.01 (d, J ) 15.4
Hz, 1H), 13.51 (s, 1H). 13C NMR δ 113.3, 119.0, 121.1, 124.0,
128.4, 129.2, 129.4, 131.8, 134.3, 139.0, 147.9, 159.0, 192.7.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-3-(2-thienyl)-2-propen-
1-one (11). 2-Thiophenecarboxaldehyde (0.47 g, 4.2 mmol) gave
1.35 g (98%) of 11 (the product was recrystallized by stirring in
refluxing EtOH followed by filtration after cooling). Mp 165-167
1
Experimental Section
°C. H NMR δ 7.15 (dd, J ) 3.5, 5.0 Hz, 1H), 7.31 (d, J ) 15.0
Hz, 1H), 7.46 (d, J ) 3.5 Hz, 1H), 7.54 (d, J ) 5.0 Hz, 1H), 7.76
(d, J ) 2.3 Hz, 1H), 7.82 (d, J ) 2.3 Hz, 1H), 8.12 (d, J ) 15.0
Hz, 1H). 13C NMR δ 113.0, 117.4, 120.8, 123.7, 128.0, 128.8,
130.7, 133.8, 138.6, 139.7, 139.9, 158.8, 191.9.
1-(3,5-Dibromo-2-hydroxyphenyl)-3-phenyl-propan-1,3-di-
one (3).56 Benzoyl chloride (0.4 g, 2.9 mmol) was added to 3,5-
dibromo-2-hydroxyacetophenone (1) (0.5 g, 1.7 mmol) in pyridine
(15 mL) and stirred for 2 h. The solution was acidified with HCl
(1 M) and extracted with CH2Cl2 (4 × 20 mL). The combined
organic phases were dried with MgSO4 before the solvent was
removed under vacuum. The residue was dissolved in pyridine (40
mL), KOH (0.2 g, 4.2 mmol) was added, and the mixture was
warmed to 50 °C for 4 h. The solution was poured into HCl (1 M),
and the precipitate was filtered off and washed with EtOH to give
0.6 g (93%) of 3. The product was used in the next step without
further characterization. Mp 120-121 °C. 1H NMR δ 6.70 (s, 1H),
7.47-7.50 (m, 2H), 7.57-7.59 (m, 1H), 7.78-7.81 (m, 2H), 7.92-
7.94 (m, 2H), 12.79 (s, 1H), 15.28 (s, 1H). 13C NMR δ 92.1, 110.7,
113.6, 120.8, 127.2, 129.0, 130.0, 132.3, 133.2, 140.7, 158.1, 179.2,
193.6.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-5-phenyl-2,4-penta-
dien-1-one (13). Cinnamic aldehyde (1.59 g, 12 mmol, 1.2 equiv)
gave 3.45 g (95%) of 13. Mp 148-149 °C. 1H NMR δ 7.06-7.15
(m, 3H), 7.37-7.42 (m, 3H), 7.52-7.54 (m, 2H), 7.74-7.81 (m,
3H), 13.59 (s, 1H). 13C NMR δ 113.1, 120.9, 122.1, 123.7, 126.4,
127.7, 128.1, 129.1, 130.0, 135.7, 138.6, 144.6, 147.6, 158.8, 192.4.
General Procedure for the Synthesis of 2-Aryl/Styryl-8-
bromo-6-chloro-3-hydroxychromones 14-19. Aqueous 30%
H2O2 (8-11 equiv) was added to a solution of the appropriate
chalcone (1.0 equiv) and aqueous 4 M NaOH (5.0 equiv) in a 1:1
mixture of MeOH and THF (20 mL/mmol chalcone) at 0 °C. The
reaction was stirred at room temperature overnight. The reaction
mixture was acidified with aqueous HCl (1 M), and the product
was filtered off. Spectroscopic and analytical data for some
representative examples of 14-19 follow.
1-(3-Bromo-5-chloro-2-hydroxyphenyl)-3-phenyl-propan-1,3-
dione (4).57 The same procedure as described above using 2 (5.2
1
g, 20.8 mmol) afforded 6.8 g (93%) of 4. Mp 113-114 °C. H
8-Bromo-6-chloro-3-hydroxy-flavone (14).38 The crude product
from 8 (440 mg, 1.3 mmol) was recrystallized from EtOH to yield
380 mg (82%) of 14. Mp 193-194 °C. 1H NMR δ 7.03 (br s, 1H),
7.52-7.59 (m, 3H), 7.93 (d, J ) 2.2 Hz, 1H), 8.19 (d, J ) 2.2 Hz,
1H), 8.37 (d, J ) 7.5 Hz, 2H). 13C NMR δ 113.4, 122.3, 124.4,
128.2 (2 C:s), 129.0 (2 C:s), 130.7, 130.8, 131.0, 136.9, 138.8,
145.9, 150.5, 172.3.
NMR δ 6.77 (s, 1H), 7.50-7.60 (m, 3H), 7.71-7.73 (m, 2H),
7.95-7.98 (m, 2H), 12.80 (s, 1H), 15.32 (s, 1H). 13C NMR δ 92.3,
113.5, 120.4, 124.2, 127.2, 127.3, 129.2, 133.2, 133.3, 138.3, 157.8,
179.4, 193.8.
6,8-Dibromo-flavone (5).58 A few drops of HCl was added to a
solution of 3 (1.2 g, 3.4 mmol) in glacial acetic acid (20 mL). The
reaction was refluxed for 14 h. The solution was poured into Na2-
CO3 (10%) and extracted with CH2Cl2 (4 × 30 mL). The combined
organic phases were washed with H2O (2 × 20 mL) and dried over
anhydrous MgSO4 before the solvent was removed under vacuum.
The residue was purified by flash chromatography on silica gel
using CH2Cl2 as eluent to afford 1.1 g (82%) of 5. Mp 173-174
°C (lit. 174-175 °C). 1H NMR δ 6.80 (s, 1H), 7.48-7.54 (m, 3H),
7.91-7.96 (m, 3H), 8.22 (d, J ) 2.1 Hz, 1H). 13C NMR δ 107.1,
113.1, 118.6, 126.0, 126.5, 127.8, 129.3, 130.8, 132.3, 139.3, 151.8,
163.5, 176.3.
8-Bromo-6-chloro-3-hydroxy-2-(2-thienyl)chromone (17). Com-
pound 11 (1.10 g, 3.2 mmol) gave 0.78 g (68%) of 17. Mp 246-
247 °C 1H NMR (DMSO-d6) δ 7.33-7.35 (m, 1H), 7.94-7.97 (m,
2H), 8.02 (d, J ) 2.3 Hz, 1H), 8.26 (d, J ) 2.3 Hz, 1H), 10.64 (br
s, 1H). 13C NMR (DMSO-d6) δ 112.4, 123.4, 123.5, 127.8, 128.5,
129.0, 131.6, 131.8, 135.5, 136.7, 143.7, 149.1, 170.3. Anal. Calcd
for C13H6BrClO3S: C, 43.66; H, 1.69. Found: C, 43.78; H, 1.65.
8-Bromo-6-chloro-3-hydroxy-2-styryl-chromone (19). The crude
product from 13 (0.87 g, 2.4 mmol) was purified by flash
chromatography using a manual gradient of CH2Cl2:diethyl ether
8-Bromo-6-chloro-flavone (6). The same procedure as described
above using 4 (1.2 g, 3.4 mmol) afforded 0.9 mg (82%) of 6. Mp
1
(100:0f95:5) to yield 0.60 g (66%) of 19. Mp 173-174 °C. H
1
NMR δ 6.51 (br s, 1H), 7.32-7.44 (m, 4H), 7.63-7.67 (m, 3H),
7.89 (d, J ) 2.5 Hz, 1H), 8.15 (d, J ) 2.5 Hz, 1H). 13C NMR δ
112.9, 115.1, 123.0, 123.9, 124.3, 127.9, 128.5, 128.9, 129.1, 129.8,
130.5, 135.7, 136.3, 136.6, 171.0. Anal. Calcd for C17H10BrClO3:
C, 54.07; H, 2.67. Found: C, 53.97; H, 2.72.
178-179 °C. H NMR δ 6.83 (s, 1H), 7.50-7.56 (m, 3H), 7.86
(d, J ) 2.6 Hz, 1H), 7.95-7.98 (m, 2H), 8.11 (d, J ) 2.6 Hz, 1H).
13C NMR δ 107.1, 113.0, 124.7, 125.7, 126.5, 129.3, 130.9, 131.4,
132.2, 136.8, 151.4, 163.7, 176.6. Anal. Calcd for C15H8BrClO2:
C, 53.69; H, 2.40. Found: C, 53.75; H, 2.46.
General Procedure for the Synthesis of the 3-O-Alkylated
Derivatives 21-25. A solution of the 2-aryl-8-bromo-6-chloro-3-
hydroxychromone (1 equiv), the appropriate alkyl bromide (1.5-
2.0 equiv), and K2CO3 (2 equiv) in DMF (volume dependent on
the solubility of the starting material) was stirred at 50 °C overnight.
(56) Banerji, K. D.; Poddar, D. J. Indian Chem. Soc. 1979, 56, 62-65.
(57) Thool, A. W.; Ghiya, B. J. J. Indian Chem. Soc. 1988, 65, 522-524.
(58) Sandulache, A.; Cascaval, A.; Toniutti, N.; Giumanini, A. G.
Tetrahedron 1997, 53, 9813-9822.
6868 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2,3,6,8-Tetrasubstituted Chromones
The solution was diluted with water and the solution was acidified
with HCl (1 M), and the precipitate was filtered off. Spectroscopic
and analytical data for some representative examples of 21-25
follow.
pure product (method A, procedure a). Mp 176-177 °C. 1H NMR
δ 3.76 (d, J ) 6.5 Hz, 2H), 5.18-5.25 (m, 2H), 6.01-6.11 (m,
1H), 7.03 (br s, 1H), 7.49-7.57 (m, 4H), 8.10 (d, J ) 2.6 Hz, 1H),
8.22-8.24 (m, 2H). 13C NMR δ 33.7, 118.1, 121.6, 122.8, 127.8,
128.8, 130.4, 130.5, 131.1, 132.2, 133.9, 134.3, 138.6, 145.1, 151.9,
172.7. Anal. Calcd for C18H13ClO3: C, 69.13; H, 4.19. Found: C,
68.85; H, 3.97.
8-Bromo-6-chloro-2-(4-methoxyphenyl)-3-[3-(N-phthalimido)-
propoxy]chromone (21). Compound 15 (0.72 g, 1.9 mmol) gave
1
0.95 g (88%) of 21. Mp 207-208 °C. H NMR δ 2.14 (m, 2H),
3.85 (t, J ) 7.3 Hz, 2H), 3.90 (s, 3H), 4.15 (t, J ) 6.3 Hz, 2H),
7.06 (d, J ) 9.1 Hz, 2H), 7.70 (dd, J ) 3.1, 5.4 Hz, 2H), 7.83 (dd,
J ) 3.1, 5.4 Hz, 2H), 7.86 (d, J ) 2.5 Hz, 1H), 8.13 (d, J ) 2.5
Hz, 1H), 8.25 (d, J ) 9.1 Hz, 2H). 13C NMR δ 29.3, 35.3, 55.4,
70.0, 112.6, 114.2, 122.7, 123.2, 124.6, 125.7, 130.6, 130.7, 132.1,
133.9, 136.2, 139.7, 150.2, 156.0, 161.9, 168.2, 173.0. Anal. Calcd
for C27H19BrClNO6: C, 57.01; H, 3.37; N, 2.46. Found: C, 56.66;
H, 3.49; N, 2.59.
8-Bromo-6-chloro-3-ethoxycarbonylmethyl-flavone (25). Com-
pound 14 (0.42 g, 1.2 mmol) gave 0.41 g (71%) of 25. Mp 124-
125 °C. 1H NMR δ 1.20 (t, J ) 7.2 Hz, 3H), 4.17 (q, J ) 7.2 Hz,
2H). 4.90 (s, 2H), 7.50-7.54 (m, 3H), 7.87 (d, J ) 2.5 Hz, 1H),
8.13 (d, J ) 2.4 Hz, 1H), 8.29-8.32 (m, 2H). 13C NMR δ 14.3,
61.3, 68.3, 113.0, 124.7, 125.7, 128.8, 129.3, 130.4, 131.1, 131.6,
136.8, 139.7, 150.4, 155.6, 169.0, 173.1. Anal. Calcd for C19H14-
BrClO5: C, 52.14; H, 3.22. Found: C, 52.00; H, 3.12.
8-Benzyl-6-chloro-3-hydroxy-2-(2-thienyl)chromone (32). Com-
pound 17 (0.36 g, 1.0 mmol) and benzylSnBu3 gave 32 which was
purified by flash chromatography using ethyl acetate, CH2Cl2 and
hexane (7:7:86) to yield 0.36 g (98%) of pure product (method A,
1
procedure b). Mp 221-222 °C. H NMR δ 4.34 (s, 2H), 6.91 (br
s, 1H), 7.22-7.36 (m, 6H), 7.40 (d, 1H, J ) 2.1 Hz), 7.62 (d, 1H,
J ) 4.8 Hz), 7.95 (d, 1H, J ) 3.4 Hz), 8.09 (d, 1H, J ) 2.1 Hz).
13C NMR δ 35.3, 122.0, 122.9, 126.9, 128.4, 128.8, 128.9, 129.8,
130.0, 130.4, 132.78, 132.83, 134.2, 136.3, 138.1, 142.7, 151.3,
171.6. Anal. Calcd for C20H13ClO3S: C, 65.13; H, 3.55. Found:
C, 65.26; H, 3.64.
3-Acetoxy-8-benzyl-6-chloro-2-(4-methoxyphenyl)chromone
(45). Compound 27 (0.41 g, 0.97 mmol) and benzylSnBu3 gave 45
which was purified by flash chromatography using ethyl acetate,
CH2Cl2, and hexane (10:10:80) to yield 0.33 g (78%) of pure
1
product (method A, procedure b). Mp 200-201 °C. H NMR δ
3-Acetoxy-8-bromo-6-chloro-2-(4-methoxyphenyl)chro-
mone (27). Acetyl chloride (0.15 mL, 2.1 mmol) was added to a
suspension of 15 (0.38 g, 1.0 mmol) and Et3N (1.0 mL, 7.2 mmol)
in CH2Cl2. The reaction was stirred overnight at room temperature.
The organic phase was washed twice with 0.2 M HCl and saturated
NaHCO3. The organic phase was dried with Na2SO2 whereafter
the solvent was removed. Yield 0.44 g (>99%). Mp 184-187 °C
1H NMR δ 2.39 (s, 3H), 3.90 (s, 3H), 7.05 (d, J ) 9.1 Hz, 2H),
7.90 (d, J ) 2.5 Hz, 1H), 8.00 (d, J ) 9.1 Hz, 2H), 8.16 (d, J )
2.5 Hz, 1H). 13C NMR δ 20.6, 55.5, 112.7, 114.4, 121.6, 124.8,
125.1, 130.3, 131.2, 132.8, 136.7, 150.5, 156.2, 162.4, 167.6, 170.4.
Anal. Calcd for C18H12BrClO5: C, 51.03; H, 2.86. Found: C, 51.26;
H, 2.94.
General Procedure for the Synthesis of Triflates Used in the
Pd Coupling Reactions. Triflic anhydride (2.0-2.5 equiv) was
added dropwise to a solution of the appropriate 3-hydroxy-
chromanone derivative and NEt3 or pyridine (5-8 equiv) in CH2-
Cl2 at 0 °C. The reaction was stirred overnight at room temperature.
The organic phase was washed twice with aqueous 0.1 M HCl and
aqueous saturated NaHCO3. The organic phase was dried with
MgSO4 or Na2SO4 whereafter the solvent was removed. The residue
was purified by flash chromatography.
2.36 (s, 3H), 3.89 (s, 3H), 4.27 (s, 2H), 6.98 (d, J ) 9.0 Hz, 2H),
7.21-7.37 (m, 5H), 7.43 (d, J ) 2.5 Hz, 1H), 7.66 (d, J ) 9.0 Hz,
2H), 8.10 (d, J ) 2.5 Hz, 1H). 13C NMR δ 20.6, 35.7, 55.4, 114.2,
122.0, 123.6, 124.7, 126.9, 128.77, 128.81, 130.0, 130.8, 132.6,
132.9, 134.5, 138.0, 152.0, 156.2, 162.0, 167.8, 171.1. Anal. Calcd
for C25H19ClO5: C, 69.05; H, 4.40. Found: C, 68.97; H, 4.44.
3,8-Diallyl-6-chloro-flavone (46). The triflate from 28 (0.21 g,
0.66 mmol) was purified by flash chromatography using CH2Cl2
1
as eluent to yield 0.16 g (55%) of pure product. H NMR δ 3.68
(d, J ) 6.5 Hz, 2H), 5.15-5.25 (m, 2H), 5.95-6.05 (m, 1H), 7.57-
7.65 (m, 4H), 7.85-7.87 (m, 2H), 8.10 (d, J ) 2.6 Hz, 1H). 13C
NMR δ 33.8, 118.4 (q, JC,F ) 321 Hz, CF3), 118.5, 123.9, 124.7,
128.5, 129.0, 129.3, 132.2, 132.4, 132.8, 134.0, 135.2, 137.9, 152.1,
158.8, 170.6. The triflate (0.16 g, 0.36 mmol) and allylSnBu3 gave
46 which was purified by flash chromatography using CH2Cl2 as
eluent to yield 0.16 g (72%) of pure product (method A, procedure
b). Mp 131-132 °C. 1H NMR δ 3.32 (d, J ) 5.6 Hz, 2H), 3.59 (d,
J ) 6.5 Hz, 2H), 5.01-5.19 (m, 4H), 5.92-6.11 (m, 2H), 7.46 (d,
J ) 2.6 Hz, 1H), 7.51-7.55 (m, 3H), 7.67-7.70 (m, 2H), 8.08 (d,
J ) 2.6 Hz, 1H). 13C NMR δ 30.2, 33.7, 115.8, 117.8, 119.5, 123.5,
123.9, 128.7, 128.8, 130.6, 130.8, 131.8., 133.1, 133.7, 134.6, 135.9,
152.7, 162.4, 177.3. Anal. Calcd for C21H17ClO2: C, 74.89; H, 5.09.
Found: C, 74.76; H, 5.04.
8-Bromo-6-chloro-3-trifluoromethylsulfonyloxy-flavone (26).
The triflate from 14 (0.36 g, 1.0 mmol) was purified by flash
chromatography using CH2Cl2 as eluent to yield 0.33 g (67%) of
26. 1H NMR δ 7.57-7.67 (m, 3H), 7.95-7.98 (m, 3H), 8.18 (d, J
) 2.6 Hz, 1H). 13C NMR δ 113.2, 118.5 (q, JC,F ) 321 Hz, CF3),
125.1, 125.2, 127.9, 129.1, 129.2, 132.4, 133.0, 133.8, 137.9, 150.6,
159.0, 169.7.
3,8-Dibenzyl-6-chloro-2-(2-thienyl)chromone (51). The triflate
from compound 32 was prepared as described for the synthesis of
49. The triflate (0.26 g, 0.52 mmol) and benzylSnBu3 gave 51 which
was purified by flash chromatography using ethyl acetate, CH2Cl2,
and hexane (5:5:90) to yield 0.16 g (69%) of pure product (method
1
A, procedure b). Mp 171-173 °C. H NMR δ 4.24 (s, 2H), 4.30
General Procedure for Stille Cross-Coupling Reactions of
Aryl Bromides and Triflates. Synthesis of 28-33, 37-40, 45-
51 (Method A). A solution of the appropriate aryl bromide or
triflate (1 equiv), Pd(PPh3)4 (0.1 equiv), and benzyl- or allylSnBu3
(1.6 equiv) in DMF was reacted (a) under N2 at 80 °C overnight,
or (b) in a microwave cavity at 160 °C for 30 min. The mixture
was filtered through Celite with ethyl acetate or a 1:1 mixture of
ethyl acetate and CH2Cl2. The filtrate was stirred with saturated
aqueous KF for 30-60 min. The phases were separated, and the
aqueous phase was extracted once with CH2Cl2. The combined
organic phases were dried over anhydrous MgSO4 or Na2SO4,
whereafter the solvent was removed. The residue was purified by
flash chromatography. Spectroscopic and analytical data for some
representative examples of 28-33, 37-40, and 45-51 follow.
8-Allyl-6-chloro-3-hydroxy-flavone (28). Compound 14 (0.70
g, 2.0 mmol) and allylSnBu3 gave 28 which was purified by flash
chromatography using CH2Cl2 as eluent to yield 0.56 g (89%) of
(s, 2H), 7.10 (m, 1H), 7.20-7.37 (m, 10H), 7.40 (d, J ) 2.5 Hz,
1H), 7.43 (d, J ) 3.5 Hz, 1H), 7.59 (d, J ) 4.9 Hz, 1H), 8.09 (d,
J ) 2.5 Hz, 1H). 13C NMR δ 31.1, 35.2, 118.6, 123.6, 123.6, 126.2,
126.8, 127.8, 128.1, 128.6, 128.8, 128.9, 130.3, 130.6, 130.6, 132.5,
134.2, 134.6, 138.1, 138.6, 152.1, 156.7, 177.1. Anal. Calcd for
C27H19ClO2S: C, 73.21; H, 4.32. Found: C, 73.08; H, 4.19.
General Procedure for Heck Reactions of Aryl Bromides.
Synthesis of 34 and 41 (Method B). A solution of the appropriate
aryl bromide (1 equiv), Pd(OAc)2 (0.1 equiv), Pd(o-tolyl)3 (0.2
equiv), NEt3 (2 equiv), and methyl acrylate (2 equiv) in DMF (4
mL) in a microwave vial was heated in a microwave cavity for 30
min at 160 °C. The mixture was filtered through Celite with ethyl
acetate. The filtrate was acidified with HCl (1 M) and extracted
twice with ethyl acetate. The combined organic phases were washed
with saturated NaHCO3, and the combined organic phases were
dried over anhydrous Na2SO4 before the solvent was removed under
vacuum. The residue was purified by flash chromatography.
J. Org. Chem, Vol. 71, No. 18, 2006 6869

Dahle´n et al.
6-Chloro-3-hydroxy-8-(2-methoxycarbonylethenyl)flavone (34).
Compound 14 (0.65 g, 1.8 mmol) gave 34 which was purified by
flash chromatography using a manual gradient of CH2Cl2:diethyl
ether (100:0f95:5) to yield 0.53 g (80%) of pure product. Mp 232-
heated in a microwave cavity for 30 min at 150 °C. The solution
was filtered through Celite, acidified, and extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were dried over
anhydrous MgSO4, and the solvent was removed under vacuum.
6-Chloro-3-hydroxy-8-naphthyl-flavone (36). The crude prod-
uct from 14 (0.15 g, 0.43 mmol) was dissolved in CH2Cl2, acetyl
chloride (0.15 mL) and NEt3 (0.8 mL) were added, and the reaction
was stirred for 14 h. HCl (1 M) was added, and the water phase
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were dried over anhydrous MgSO4, and the solvent was
removed under vacuum. The residue was purified by flash chro-
matography using a manual gradient of CH2Cl2:diethyl ether (100:
0f95:5) to afford 3-acetoxy-6-chloro-8-naphthyl-flavone. 1H NMR
δ 2.39 (s, 3H), 7.37-7.46 (m, 3H), 7.54-7.58 (m, 2H), 7.69-
7.78 (m, 4H), 7.88-7.97 (m, 3H), 8.07 (s, 1H), 8.24 (d, J ) 2.6
Hz, 1H). 13C NMR δ 20.8, 124.7, 125.3, 126.9, 127.08, 127.13,
128.0, 128.3, 128.4, 128.5, 128.9, 129.2, 129.8, 131.4, 131.7, 132.1,
133.3, 133.4, 133.8, 134.0, 135.1, 151.3, 156.3, 168.0, 171.5. The
resulting 3-acetoxy-6-chloro-8-naphthyl-flavone was directly added
to NaOMe (1 M, 2 mL) in MeOH (20 mL) and stirred for 5 h. The
solution was acidified HCl (1 M) and extracted with CH2Cl2 (4 ×
20 mL). The combined organic phases were dried over anhydrous
MgSO4, and the solvent was removed under vacuum. The residue
was purified by flash chromatography using a manual gradient of
CH2Cl2:diethyl ether (100:0f95:5) to give 0.14 g (79%) of 36.
Mp 216-217 °C. 1H NMR δ 7.08 (br s, 1H), 7.38-7.40 (m, 3H),
7.57-7.63 (m, 2H), 7.77 (dd, J ) 1.4, 8.4 Hz, 1H), 7.81 (d, J )
2.6 Hz, 1H), 7.92-7.98 (m, 2H), 8.01 (d, J ) 8.4 Hz, 1H), 8.09-
8.11 (m, 2H), 8.15 (s, 1H), 8.26 (d, J ) 2.6 Hz, 1H). 13C NMR δ
122.3, 124.0, 127.0, 127.1, 127.3, 128.0, 128.1, 128.4, 128.9, 129.3,
130.6, 130.8, 131.0, 132.3, 133.4, 133.5, 134.2, 134.8, 138.8, 145.5,
151.1, 172.8. Anal. Calcd for C25H15ClO3: C, 75.29; H, 3.79.
Found: C, 75.36; H, 3.71.
1
233 °C. H NMR δ 3.88 (s, 3H), 6.70 (d, J ) 16.1 Hz, 1H), 6.97
(br s, 1H), 7.50-7.60 (m, 3H), 7.87 (d, J ) 2.5 Hz, 1H), 8.21-
8.25 (m, 4H). 13C NMR δ 52.4, 122.5, 122.9, 126.6, 127.0, 128.0,
129.1, 130.7, 130.8, 130.9, 132.0, 135.7, 138.8, 145.8, 151.5, 166.7,
172.4. Anal. Calcd for C19H13ClO5: C, 63.97; H, 3.67. Found: C,
63.94; H, 3.61.
6-Chloro-8-(2-methoxycarbonylethenyl)-3-[3-(N-phthalimido)-
propoxy]flavone (41). Compound 20 (0.30 g, 0.55 mmol) gave
41 which was purified by flash chromatography using a manual
gradient of CH2Cl2:diethyl ether (100:0f95:5) to yield 0.26 g (87%)
of pure product. Mp 187-188 °C. 1H NMR δ 2.05-2.10 (m, 2H),
3.77 (t, J ) 7.3 Hz, 2H), 3.84 (s, 3H), 4.16 (t, J ) 6.2 Hz, 2H),
6.67 (d, J ) 16.1 Hz, 1H), 7.49-7.57 (m, 3H), 7.67-7.69 (m,
2H), 7.79 (m, 3H), 8.05-8.08 (m, 2H), 8.11 (d, J ) 16.1 Hz, 1H),
8.18 (d, J ) 2.6 Hz, 1H). 13C NMR δ 29.4, 35.4, 52.2, 70.5, 122.7,
123.4, 126.0, 126.6, 127.0, 128.91, 128.94, 130.5, 130.9, 131.3,
131.8, 132.3, 134.0, 135.8, 140.7, 151.5, 156.3, 166.7, 168.4, 173.6.
Anal. Calcd for C30H22ClNO7: C, 66.24; H, 4.08; N, 2.58. Found:
C, 66.34; H 3.94; N, 2.53.
General Procedure for Sonogashira Reactions of Bromides.
Synthesis of 35, 42, and 44 (Method C). CuI (0.1 equiv) was
added to a suspension of the appropriate aryl bromide (1.0 equiv),
PdCl2(PPh3)2 (0.1 equiv), NEt3 (10 equiv), and TMS-acetylene or
N-Boc-propargylamine (2.0 equiv) in THF (15 mL). The mixture
was heated in a microwave cavity for 30 min at 120 °C. The solution
was filtered through Celite. NaHCO3 was added and extracted four
times with CH2Cl2. The combined organic phases were dried over
anhydrous MgSO4 and the solvent was removed under vacuum.
The residue was purified by flash chromatography.
6-Chloro-3-hydroxy-8-(2-trimethylsilylethynyl)flavone (35).
Compound 14 (0.24 g, 0.67 mmol) gave 35 which was purified by
flash chromatography using CH2Cl2 as eluent to yield 0.18 g (71%)
6-Chloro-8-naphthyl-3-[3-(N-phthalimido)propoxy]flavone (43).
Compound 20 (0.19 g, 0.34 mmol) gave 43 which was purified by
flash chromatography using CH2Cl2 as eluent to yield 0.22 g (86%)
of pure product. Mp 204-206 °C.1H NMR δ 2.11 (m, 2H), 3.84
(t, J ) 7.3 Hz, 2H), 4.21 (t, J ) 6.2 Hz, 2H), 7.38-7.41 (m, 3H),
7.56-7.59 (m, 2H), 7.70-7.84 (m, 6H), 7.91-8.03 (m, 5H), 8.13
(s, 1H), 8.24 (d, J ) 2.2 Hz, 1H). 13C NMR δ 29.5, 35.5, 70.4,
123.4, 124.4, 125.9, 126.9, 127.0, 127.3, 128.0, 128.3, 128.4, 128.7,
128.9, 129.2, 130.75, 130.83, 131.1, 132.29, 132.34, 133.24, 133.4,
133.8, 134.0, 134.5, 140.7, 150.9, 155.9, 168.4, 174.2. Anal. Calcd
for C36H24ClNO5: C, 73.78; H, 4.13; N, 2.39. Found: C, 73.81;
H, 4.11; N, 2.33.
6-Allyl-8-benzyl-3-[3-(N-phthalimido)propoxy]flavone (53). A
solution of 37 (0.19 g, 0.35 mmol), allylSnBu3 (0.17 g, 0.52 mmol),
Pd2dba3 (0.01 g, 0.01 mmol), and P(tert-Bu)3 (8 mg, 0.04 mmol)
in dioxane (15 mL) under N2 was warmed to 80 °C for 14 h. The
mixture was allowed to cool to RT and filtered through Celite. A
saturated aqueous KF solution (10 mL) was added, and the stirring
was continued for 30 min. The solution was extracted with CH2-
Cl2 (4 × 20 mL). The combined organic phases were washed with
H2O (2 × 10 mL) and dried over anhydrous MgSO4 before the
solvent was removed under vacuum. The residue was purified by
flash chromatography using a manual gradient of CH2Cl2:diethyl
ether (100:0f95:5) as eluent to afford 0.15 g (77%) of 53. Mp
140-142 °C. 1H NMR δ 2.06-2.13 (m, 2H), 3.47 (d, J ) 6.6 Hz,
2H), 3.80 (t, J ) 7.2 Hz, 2H), 4.13 (t, J ) 6.2 Hz, 2H), 4.29 (s,
2H), 5.09-5.13 (m, 2H), 5.93-6.03 (m, 1H), 7.22-7.34 (m, 6H),
7.45-7.48 (m, 3H), 7.69-7.71 (m, 2H), 7.81-7.83 (m, 2H), 7.87-
7.89 (m, 2H), 7.96 (d, J ) 2.2 Hz, 1H). 13C NMR δ 29.5, 35.6,
36.2, 39.8, 70.3, 116.8, 120.9, 123.4, 123.5, 126.7, 127.6, 128.6,
128.8, 128.9, 129.8, 130.4, 130.8, 131.3, 132.4, 134.0, 135.4, 136.8,
139.5, 140.5, 152.3, 155.7, 168.4, 175.4. Anal. Calcd for C36H29-
NO5: C, 77.82; H, 5.26; N, 2.52. Found: C, 77.88; H, 5.22; N,
2.37.
1
of pure product. Mp 248-249 °C. H NMR δ 0.37 (s, 9H), 7.01
(br s, 1H), 7.49-7.56 (m, 3H), 7.77 (d, J ) 2.5 Hz, 1H), 8.15 (d,
J ) 2.5 Hz, 1H), 8.38-8.40 (m, 2H). 13C NMR δ -0.1, 97.0, 104.4,
116.3, 121.6, 125.0, 128.2, 128.9, 130.1, 130.8, 131.0, 136.9, 138.9,
145.3, 154.0, 172.5. Anal. Calcd for C20H17ClO3Si: C, 65.12; H,
4.65. Found: C, 65.22; H, 4.62.
6-Chloro-3-[3-(N-phthalimido)propoxy]-8-(2-trimethylsilyl-
ethynyl)flavone (42). Compound 20 (0.19 g, 0.34 mmol) gave 42
which was purified by flash chromatography using CH2Cl2 as eluent
1
to yield 0.18 g (91%). Mp 145-146 °C H NMR δ 0.32 (s, 9H),
2.11-2.18 (m, 2H), 3.84 (t, J ) 7.3 Hz, 2H), 4.17 (t, J ) 6.3 Hz,
2H), 7.49-7.54 (m, 3H), 7.67-7.71 (m, 3H), 7.78-7.82 (m, 2H),
8.08 (d, J ) 2.6 Hz, 1H), 8.27-8.29 (m, 2H). 13C NMR δ -0.1,
29.5, 35.4, 70.4, 97.0, 104.1, 115.9, 123.3, 125.2, 125.4, 128.7,
129.1, 130.2, 130.8, 131.3, 132.3, 134.0, 136.6, 140.9, 153.9, 155.5,
168.4, 173.8. Anal. Calcd for C31H26ClNO5Si: C, 66.96; H, 4.71;
N, 2.52. Found: C, 67.08; H, 4.63; N, 2.42.
8-[(3-(tert-Butoxycarbonylamino)-1-propynyl]-6-chloro-3-[eth-
oxycarbonylmethyl]flavone (44). Compound 25 (0.10 g, 0.22
mmol) gave 44 which was purified by flash chromatography using
CH2Cl2 as eluent to yield 0.09 g (83%) of pure product. Mp 158-
159 °C 1H NMR δ 1.21 (t, J ) 7.1 Hz, 3H), 1.48 (s, 9H), 4.18 (q,
J ) 7.1 Hz, 2H), 4.28 (d, J ) 5.4 Hz, 2H), 4.89 (s, 2H), 4.94 (s,
1H), 7.52-7.58 (m, 3H), 7.66 (d, J ) 2.6 Hz, 1H), 8.10 (d, J )
2.6 Hz, 1H), 8.28-8.31 (m, 2H). 13C NMR δ 14.2, 28.5, 31.3, 61.2,
68.3, 75.7, 80.4, 94.5, 115.5, 124.9, 125.1, 128.7, 129.1, 130.3,
130.5, 131.3, 136.5, 139.7, 153.5, 155.2, 155.3, 168.9, 173.3. Anal.
Calcd for C27H26ClNO7: C, 63.34; H, 5.12; N, 2.74. Found: C,
63.23; H, 5.01; N, 2.58.
General Procedure for Suzuki Reactions of Aryl Bromides.
Synthesis of 36 and 43 (Method D). A mixture of the appropriate
aryl bromide (1.0 equiv), 2-naphthylboronic acid (1.2 equiv), Cs2-
CO3 (2.5 equiv), and Pd(PPh3)4 (0.1 equiv) in DMF (15 mL) was
General Procedure for the Heck Reactions of Aryl Chlorides.
Synthesis of 54-57. NEt3 (2.0 equiv) was added to a suspension
6870 J. Org. Chem., Vol. 71, No. 18, 2006

Synthesis of 2,3,6,8-Tetrasubstituted Chromones
of the appropriate aryl chloride (1.0 equiv), Pd2(dba)3 (0.03 equiv),
methyl acrylate (2.5 equiv), and P(t-Bu)3BF4 (0.12 equiv) in dioxane
(4 mL) under N2 in a microwave tube. The mixture was heated in
a microwave cavity for 30 min at 160 °C. The solution was filtered
through Celite with ethyl acetate, and H2O was added. The mixture
was extracted four times with ethyl acetate. The combined organic
phases were dried over anhydrous MgSO4 before the solvent was
removed under vacuum. The residue was purified by flash chro-
matography using a manual gradient of CH2Cl2:diethyl ether (100:
0f95:5). Spectroscopic and analytical data for some representative
examples of 54-57 follow.
3.89 (s, 3H), 4.38 (s, 2H), 6.47 (d, J ) 15.7 Hz, 1H), 6.90 (s, 1H),
7.01 (d, J ) 9.2 Hz, 2H), 7.21-7.36 (m, 5H), 7.58 (d, J ) 1.8 Hz,
1H), 7.72 d, J ) 15.7 Hz, 1H), 8.05 (d, J ) 9.2 Hz, 2H), 8.29 (d,
J ) 1.8 Hz, 1H). 13C NMR δ 36.0, 52.1, 55.6, 114.4, 119.2, 123.6,
124.1, 127.1, 129.0, 129.1, 129.7, 130.9, 131.7, 133.1, 138.0, 138.6,
143.3, 145.7, 154.3, 161.4, 167.3, 173.1. Anal. Calcd for
C27H22O6: C, 73.29; H, 5.01. Found: C, 73.40; H, 4.88.
8-Benzyl-3-[3-(tert-butoxycarbonylamino)propoxy]-6-chloro-
flavone (52). Ethylenediamine (2 mL) was added to a solution of
37 (0.44 g, 0.8 mmol) in EtOH (30 mL) heated to reflux and stirred
for 5 h. The mixture was allowed to cool, and K2CO3 (10%) was
added to pH > 12. The solution was extracted with diethyl ether
(4 × 15 mL), and the combined organic phases were dried over
anhydrous Na2SO4 before the solvent was removed under vacuum.
The residue was dissolved in THF (10 mL) and MeOH (10 mL),
di-tert-butyl dicarbonate (0.50 g, 2.3 mmol) in THF (5 mL) was
added, and the reaction was refluxed for 14 h. The solution was
cooled, and H2O (10 mL) was added. After extraction with CH2-
Cl2 (4 × 15 mL), the combined organic phases were dried over
anhydrous Na2SO4 before the solvent was removed under vacuum.
The residue was purified by flash chromatography with a manual
gradient using CH2Cl2:diethyl ether (100:0f95:5) as eluent to give
8-Benzyl-3-[3-(tert-butoxycarbonylamino)propoxy]-6-(2-meth-
oxycarbonylethenyl)flavone (56). Compound 52 (0.08 g, 0.14
1
mmol) gave 0.07 g (85%) of 56. Mp 133-134 °C. H NMR δ
1.46 (s, 9H), 1.85-1.88 (m, 2H), 3.37-3.39 (m, 2H), 3.82 (s, 3H),
4.01 (t, J ) 5.9 Hz, 2H), 4.32 (s, 2H), 5.66 (s, 1H), 6.48 (d, J )
16.1 Hz, 1H), 7.22-7.36 (m, 5H), 7.46-7.51 (m, 3H), 7.61 (d, J
) 2.2 Hz, 1H), 7.73 (d, J ) 16.1, 1H), 7.86-7.88 (m, 2H), 8.30
(d, J ) 2.2 Hz, 1H). 13C NMR δ 28.7, 30.2, 36.1, 37.3, 52.0, 69.9,
79.0, 119.3, 124.4, 124.7, 127.0, 128.7, 128.8, 128.9, 129.0, 130.8,
131.1, 131.6, 133.3, 138.6, 140.7, 143.2, 154.4, 156.2, 156.4, 167.2,
175.2. Anal. Calcd for C34H35NO7: C, 71.69; H, 6.19; N, 2.46.
Found: C, 71.58; H, 6.10; N, 2.38.
1
0.36 g (87%) of 52. Mp 166-167 °C. H NMR δ 1.45 (s, 9H),
3,8-Dibenzyl-6-(2-methoxycarbonylethenyl)-2-thienyl-
chromone (57). Compound 51 (0.09 g, 0.20 mmol) gave 0.08 g
1.83-1.87 (m, 2H), 3.35-3.39 (m, 2H), 3.99 (t, J ) 5.9 Hz, 2H),
4.28 (s, 2H), 5.63 (s, 1H), 7.21-7.36 (m, 5H), 7.41 (d, J ) 2.6
Hz, 1H), 7.46-7.51 (m, 3H), 7.85-7.87 (m, 2H), 8.12 (d, J ) 2.6
Hz, 1H). 13C NMR δ 28.7, 30.2, 36.0, 37.3, 69.9, 79.1, 123.7, 125.5,
127.1, 128.7, 128.8, 129.0, 129.1, 130.7, 130.9, 131.2, 132.8, 134.5,
138.3, 140.6, 152.0, 156.4, 156.5, 174.5. Anal. Calcd for C30H30-
ClNO5: C, 69.29; H, 5.81; N, 2.69. Found: C, 69.22; H, 5.74; N,
2.61.
1
(76%) of 57. Mp 184-185 °C. H NMR δ 3.80 (s, 3H), 4.25 (s,
2H), 4.33 (s, 2H), 6.45 (d, J ) 16.1 Hz, 1H), 7.09-7.11 (m, 1H),
7.19-7.34 (m, 10H), 7.43 (d, J ) 3.3 Hz, 1H), 7.57-7.59 (m,
2H), 7.70 (d, J ) 15.8 Hz, 1H), 8.27 (d, J ) 1.8 Hz, 1H). 13C
NMR δ 31.3, 35.6, 52.0, 119.0, 119.1, 123.0, 124.5, 126.5, 127.0,
128.1, 128.3, 128.9, 129.0, 129.1, 130.5, 130.9, 131.2, 131.4, 133.4,
134.9, 138.7, 138.9, 143.4, 154.8, 156.8, 167.3, 178.0. Anal. Calcd
for C31H24O4S: C, 75.59; H, 4.91. Found: C, 75.51; H, 4.90.
8-Benzyl-6-(2-methoxycarbonylethenyl)-2-(4-methoxyphenyl)-
chromone-3-ol (58). Compound 55 (0.05 g, 0.10 mmol) was added
to a solution of NaOMe (1 M in MeOH, 2 mL) in MeOH and stirred
for 5 h. The solution was acidified and extracted with CH2Cl2 (2
× 20 mL). The combined organic layers were washed with saturated
NaHCO3 (2 × 20 mL) and dried over anhydrous MgSO4 before
the solvent was removed under vacuum. The residue was purified
by column chromatography (CH2Cl2:diethyl ether, 95:5) to give
0.044 g (>98%) of 58. Mp 220-222 °C. 1H NMR δ 3.82 (s, 3H),
Acknowledgment. Financial support was obtained from The
Knut and Alice Wallenberg Foundation, The Swedish Research
Council, and The Academy of Finland. We also thank Lovisa
Zander for assistance in the synthetic work.
Supporting Information Available: Compound characterization
data for compounds 9, 10, 12, 15, 16, 18, 22-24, 29-31, 33, 37-
40, 47-50, 54, 55. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO061008F
J. Org. Chem, Vol. 71, No. 18, 2006 6871