Cascade synthesis of polyoxygenated 6H,11H-[2]benzopyrano-[4,3-c][1] benzopyran-11-ones

Article abstract of DOI:10.1021/jo062592v

(Chemical Equation Presented) 2-(Methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids, reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin derivatives in good to high yields. These compounds underwent a cascade sequence of reactions, deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H, 11H-[2]benzopyrano-[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against human epithelial mammary HBL100 cells.

Full text of DOI:10.1021/jo062592v

Cascade Synthesis of Polyoxygenated
6H,11H-[2]Benzopyrano-[4,3-c][1]benzopyran-11-ones
Mikael I. Naumov,† Sergey A. Sutirin,† Andrey S. Shavyrin,‡ Olga G. Ganina,§,|
Irina P. Beletskaya,§ Ve´ronique Bourgarel-Rey, Se´bastien Combes,|
Jean-Pierre Finet,*,| and Alexey Yu. Fedorov*,†
Department of Chemistry, Nizhnyi NoVgorod N. I. LobacheVsky State UniVersity, 23 Gagarin AVenue,
603950 Nizhnyi NoVgorod, Russia, G. A. RazuVaeV Institute of Organometallic Chemistry,
Russian Academy of Science, Tropinina st. 49, 603600 Nizhnyi NoVgorod, Russia,
Department of Chemistry, Moscow State LomonosoV UniVersity, VorobyeVy Gory,
119992 Moscow, Russia, UMR 6517, CNRS et Aix-Marseille UniVersite´, CBRL,
Faculte´ des Sciences Saint-Je´roˆme, 13397 Marseille Cedex 20, France,
and FRE 2737, CNRS et Aix-Marseille UniVersite´, CISMET,
Faculte´ de Pharmacie, 13385 Marseille Cedex 5, France
afnn@rambler.ru; jean-pierre.finet@up.uniV-mrs.fr
ReceiVed December 18, 2006
2-(Methoxymethoxymethyl)aryllead triacetates, obtained in situ from the corresponding arylboronic acids,
reacted with 4-hydroxycoumarins, leading to 3-(2-methoxymethoxymethyl)aryl-4-hydroxycoumarin
derivatives in good to high yields. These compounds underwent a cascade sequence of reactions,
deprotection-halogenation-annulation, to afford polyoxygenated tetracyclic 6H,11H-[2]benzopyrano-
[4,3-c] [1]benzopyran-11-ones in good yields. Some compounds showed a moderate cytotoxicity against
human epithelial mammary HBL100 cells.
Introduction
of pharmacological activities, including antitumoral, antibacte-
rial, and antiviral (anti-HIV-1) properties. Acetylcholinesterase
inhibitory activities potentially interesting for the treatment of
neurodegenerative diseases such as Alzheimer’s disease have
been also reported.6 The biological activities of these polycyclic
Substituted furano-,1 benzofurano-,2 pyrano-,3 and indolo-
coumarins4 and their isostructural analogs5 are present in plant,
microorganism, and animal sources and manifest a wide range
† Nizhnyi Novgorod N. I. Lobachevsky State University.
‡ G. A. Razuvaev Institute of Organometallic Chemistry.
§ Moscow State Lomonosov University.
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Wang, W.; Zhao, Y.-Y.; Liang, H.; Jia, Q.; Chen, H.-B. J. Nat. Prod. 2006,
69, 876. (c) He, J.; Chan, L.; Heber, D.; Shi, W.; Lu, Q.-Y. J. Nat. Prod.
2006, 69, 121.
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Nishino, H.; Furukawa, H. Cancer Lett. 2001, 169, 15. (b) Zhang, J.-X.;
Fong, W.-F.; Wu, J. Y.-C.; Yang, M.; Cheung, H.-Y. Planta Med. 2003,
69, 223. (c) Ito, C.; Itoigawa, M.; Mishina, Y.; Filho, V. C.; Enjo, F.;
Tokuda, H.; Nishino, H.; Furukawa, H. J. Nat. Prod. 2003, 66, 368. (d)
Lopez-Perez, J. L.; Olmedo, D. A.; Olmo, E.; Vasquez, Y.; Solis, P. N.;
Gupta, M. P.; Feliciano, A. S. J. Nat. Prod. 2005, 68, 369. (e) Widelski, J.;
Melliou, E.; Fokialakis, N.; Magiatis, P.; Glowniak, K.; Chinou, I. J. Nat.
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| CNRS et Aix-Marseille Universite´, CBRL, Faculte´ des Sciences Saint-
Je´roˆme.
CNRS et Aix-Marseille Universite´, CISMET, Faculte´ de Pharmacie.
(1) (a) Kang, S. Y.; Lee, K. Y.; Sung, S. H.; Park, M. J.; Kim, Y. C. J.
Nat. Prod. 2001, 64, 683. (b) Motai, T.; Daikonya, A.; Kitanaka, S. J. Nat.
Prod. 2004, 67, 432. (c) Appendino, G.; Bianchi, F.; Bader, A.; Campag-
nuolo, C.; Fattorusso, E.; Taglialatela-Scafati, O.; Blanco-Molina, M.;
Macho, A.; Fiebich, B. L.; Bremner, P.; Heinrich, M.; Ballero, M.; Munoz,
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M.; Wang, N.-H.; Baba, K. Chem. Pharm. Bull. 2005, 53, 701. (e) Matsuda,
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10.1021/jo062592v CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/28/2007
J. Org. Chem. 2007, 72, 3293-3301
3293

Naumov et al.
SCHEME 1
SCHEME 2
coumarin-containing heterocycles are strongly dependent
upon the number and positions of alkoxyl and/or hydroxyl
substituents.1-5 Although these compounds are seldom isolated
from natural sources, relatively few examples of synthesis of
these types of biologically active compounds have been devised.
Here we describe a flexible synthetic pathway to polyoxygenated
tetracyclic 6H,11H-[2]benzopyrano-[4,3-c][1]benzopyran-11-
ones 1, which are built up by the combination of polymethoxy-
containing coumarin and 1H-2-benzopyran structural subunits.
SCHEME 3. Synthesis of Arylboronic Acids 10a-da
Two approaches to these benzopyrano-[4,3-c][1]benzopyran-
11-ones have been reported.7,8 In the first one, the key step is
a free-radical type of cyclization performed on 4-(2′-bromoben-
zyloxy)benzopyran-2-ones.7 This method was useful for the
synthesis of non-substituted or alkyl-substituted tetracyclic
isochromanocoumarin type compounds. However, the synthesis
of polyoxygenated derivatives was not reported. The second
approach to this type of compounds was recently developed in
our group.8 It involves the arylation reaction of 4-hydroxycou-
marins with 2-(halogenomethyl)aryllead triacetates 2 (X ) CH2-
Hal), derived from arylboronic acids (Scheme 1). However, the
scope of this method is restricted by the accessibility to
polyoxygenated 2-(halogenomethyl)arylboronic acids and their
poor stability. Moreover, despite the attractiveness of this
cascade procedure, the yields of final products were moderate.
a Reaction conditions: (i) NaBH4, THF/MeOH/H2O, rt; (ii) NaH, THF,
0 °C, 10 min, then ClCH2OCH3, 50 °C, 4 h; (iii) nBuLi, THF, -78 °C,
then B(OiPr)3, -78 °C, 1.5 h, then rt, overnight.
On the other hand, application of aryl derivatives of main-group
metal elements, containing easily functionalizable groups in the
ortho position of the aryl moiety, allowed the synthesis of a
variety of heterocyclic systems, via a cascade sequence of
reactions with a ligand coupling reaction as one of the key steps
(Scheme 1).8-10 Therefore, elaboration of polyfunctionalized
arylation agents, in which the aryl moiety possess two different
electrophilic centers with selective reactivities, is of significant
interest for synthetic organic chemistry.
(4) (a) Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254. (b) Boger,
D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem.
Soc. 1999, 121, 54. (c) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick,
M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479. (d) Soenen, D. R.; Hwang, I.;
Hedrick, M. P.; Boger, D. L. Bioorg. Med. Chem. Lett. 2003, 13, 1777. (e)
Iwao, M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron
Lett. 2003, 44, 4443. (f) Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.;
Wongbundit, S.; Ruchirawat, C. Angew. Chem., Int. Ed. 2004, 43, 866.
(5) (a) Zaharevitz, D. W.; Gussio, R.; Leost, M.; Senderowicz, A. M.;
Lahusen, T.; Kunick, C.; Meijer, L.; Sausville, E. A. Cancer Res. 1999,
59, 2566. (b) Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio,
R.; Sausville, E. A.; Meijer, L.; Kunick, C. J. Med. Chem. 1999, 42, 2909.
(c) Kunick, C.; Schultz, C.; Lemcke, T.; Zaharevitz, D. W.; Gussio, R.;
Jalluri, R. K.; Sausville, E. A.; Leost, M.; Meijer, L. Bioorg. Med. Chem.
Lett. 2000, 10, 567. (d) Huve, A.; Mazitschek, R.; Giannis, A. Angew.
Chem., Int. Ed. 2003, 42, 2122.
Results and Discussion
The key step for the synthesis of type 1 compounds is the
preparation of an arylating agent able to generate the synthetic
equivalent of the dicationic synthon A (Scheme 2). We
considered that application of 2-(methoxymethoxymethyl)-
aryllead triacetates C instead of the unstable 2-(halogenom-
ethyl)aryllead triacetates8 B could importantly contribute to
broadening the scope of this synthetic pathway to the synthesis
of type 1 compounds Via reductive ligand coupling reactions.11
The methoxymethyl (MOM) protecting group should afford
(6) Shun, S.; Kong, L.-Y.; Zhang, H.-Q.; He, S.-A.; Niwa, M. Hetero-
cycles 2004, 63, 271.
(7) Majumdar, K. C.; Basu, P. K.; Mukhopadhyay, P. P.; Sarkar, S.;
Ghosh, S. K.; Biswas, P. Tetrahedron 2003, 59, 2151.
(8) (a) Naumov, M. I.; Ganina, O. G.; Shavirin, A. S.; Beletskaya, I. P.;
Finet, J.-P.; Fedorov, A. Yu. Synthesis 2005, 1178. (b) Fedorov, A. Yu.;
Finet, J.-P.; Ganina, O. G.; Naumov, M. I.; Shavyrin, A. S. Russ. Chem.
Bull. 2005, 54, 2602.
(9) Ganina, O. G.; Zamotaeva, S. G.; Nosarev, M. A.; Kosenkova, O.
V.; Naumov, M. I.; Shavyrin, A. S.; Finet, J.-P.; Fedorov, A. Yu. Russ.
Chem. Bull. 2005, 54, 1606.
(10) Mar’yasin, B. A.; Shavyrin, A. S.; Finet, J.-P.; Fedorov, A. Yu.
Russ. Chem. Bull. 2006, 55, 1612.
3294 J. Org. Chem., Vol. 72, No. 9, 2007

6H,11H-[2]Benzopyrano-[4,3-c][1]benzopyran-11-ones
TABLE 1. Synthesis of Aryl Halides 8a-d and 9a-d and
Arylboronic Acids 10a-d
SCHEME 4. Reactions of Arylboronic Acids 10a-d and
Synthesis of 3-Aryl-4-hydroxycoumarins 17-20a
no.
halide
R1
R2
yield (%)
8a
8b
8c
8d
9a
9b
9c
9d
10a
10b
10c
10d
I
OBn
OMe
OH
OMe
OBn
OMe
OMOM
OMe
OBn
OMe
OMe
OMe
OH
OMe
OMe
OMe
OMOM
OMe
OMe
OMe
OMOM
91
97
69
78
65
81
38
36
61
55
38
41
Br
Br
Br
I
Br
Br
Br
OMe
OMOM
OMe
more easily handled reagents with the possibility of selective
derivatization at a later stage of the sequence of reactions.
The 2-(methoxymethoxymethyl)arylboronic acids 10a-d,
necessary for the synthesis of the appropriate aryllead triacetates,
were prepared in three steps from 2-halogenobenzaldehydes 7a-
d12 (Scheme 3). Reduction of the carbonyl function of com-
pounds 7a-d and protection of the benzylic alcohol as a MOM-
ether followed by a sequence of bromine-lithium exchange and
transmetallation afforded the arylboronic acids 10a-d in
relatively good yields (Table 1). The yields of aryl halides 9c
and 9d, containing two methoxymethyl fragments in the benzylic
and phenolic positions, were relatively lower than the yields of
the 9a and 9b analogs, bearing only one MOM group on the
benzylic position of the molecules (Table 1). A similar trend
was also observed for the subsequent conversion of these
compounds into the corresponding arylboronic acids 10a, 10b
and 10c, 10d.
Two pathways can be envisioned to transform the MOM-
protected arylboronic acids 10a-d into the aryllead triacetates
that are required for the synthesis of benzopyranocoumarins 1.
In the first route, direct deprotection of the MOM group13 should
give 2-(hydroxymethyl)arylboronic acids 11, which could be
transformed into the corresponding 2-(halogenomethyl)arylbo-
ronic acids 12 (Scheme 4, route a). Then, boron-to-lead
transmetallation should give access to type B aryllead reagents,
capable of transferring the 2-(halogenomethyl)aryl fragment on
the C-3 position of the 4-hydroxycoumarin skeleton. The 3-aryl-
4-hydroxycoumarin intermediates thereby generated could
undergo spontaneous annelation to afford type 1 tetracyclic
compounds. However, when organoboron compounds 10a and
10b were treated with concentrated HCl or HBr in acetone,
formation of the corresponding 2-(halogenomethyl)arylboronic
acids 12a and 12b was not observed (Scheme 4, route a).
Instead, the first formed 2-(hydroxymethyl)arylboronic acids 11a
and 11b underwent spontaneous acid-catalyzed cyclization to
afford the benzoxaborole derivatives 13a and 13b respectively.
Unfortunately, all attempts of boron-to-lead transmetallation
performed on organoboron compounds 13a and 13b met with
failure.
a Reaction Conditions: (i) conc HCl, acetone, 40 °C; (ii) Pb(OAc)4,
Hg(OAc)2 (0.1 equiv), CHCl3, 40 °C, 1.5 h, then rt overnight; (iii) pyridine,
CHCl3, 60 °C.
On the other hand, direct boron-to-lead transmetallation
reaction between the MOM-protected arylboronic acids 10a-d
(Scheme 4, route b) and lead tetraacetate performed in the
presence of a catalytic amount of Hg(OAc)2, according to
Pinhey’s procedure,14 generated in situ the aryllead triacetates
14a-d. Subsequent treatment of these aryllead triacetates
14a-d with 4-hydroxycoumarins 15a-c in the presence of
pyridine afforded the different 3-aryl-4-hydroxycoumarins 17-
20 in good to high yields (Table 2). The latter step involves a
reductive coupling C-arylation reaction on the R-position of the
enolized substrate through formation of a covalent organolead
intermediate 16.11,15 Although organolead-mediated arylation
reactions sometimes give complex mixtures of mono- and
polyarylated products,11,15b,16 only mono-R-arylation products
17-20 were isolated in all of the presently reported cases. One
should note that 3-aryl-4-hydroxycoumarins 17c and 18c,
derived from 4-hydroxy-6,7-dimethoxycoumarin 15c, were
(11) Finet, J.-P. Ligand Coupling Reactions with Heteroatomic Com-
pounds; Pergamon Press: Oxford, 1998.
(12) (a) Olivera, R.; SanMartin, R.; Dominguez, E.; Solans, X.; Urtiaga,
M. K.; Arriortua, M. I. J. Org. Chem. 2000, 65, 6398. (b) Fukuyama, Y.;
Yaso, H.; Mori, T.; Takahashi, H.; Minami, H.; Kodama, M. Heterocycles
2001, 54, 259. (c) Lai, C.-H.; Shen, Y.-L.; Wang, M.-N.; Rao, N. S. K.;
Liao, C.-C. J. Org. Chem. 2002, 67, 6493. (d) Bulavka, V. N.; Tolkachev,
O. N.; Shchavlinskii, A. N. Khim. Farm. Zh. 1990, 24, 59; Chem. Abstr.
1990, 113, 190833.
(13) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; J. Wiley and Sons: New York, 1999.
(14) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990, 715.
J. Org. Chem, Vol. 72, No. 9, 2007 3295

Naumov et al.
TABLE 2. Synthesis of Derivatives 17-20
SCHEME 5. Cyclization of the 3-Aryl-4-hydroxycoumarins
17-20a
no.
R1
R2
R3
R4
yield (%)
17a
17b
17c
18a
18b
18c
19a
19b
20a
20b
OBn
OBn
OBn
OMe
OMe
OMe
OMOM
OMOM
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
H
82
70
51
78
62
42
62
67
48
45
OMOM
OMOM
isolated in lower yields than their analogs 17a and 18a obtained
from 5,6,7-trimethoxycoumarin 15a and also lower than 17b
and 18b derived from 5,7-dimethoxycoumarin 15b. Use of polar
aprotic solvents17 (DMF, DMA, DMSO) did not improve the
yields of 17c and 18c or even of their analogs 17a, 17b and
18a, 18b. It is likely that the 5-methoxy group present in
substrates 15a and 15b plays a role, as it can compete with the
side chain MOM group for coordinating the lead atom during
formation of intermediate 16. By contrast, in absence of the
5-methoxy group, the MOM group can stabilize the aryloxylead-
(IV) intermediate 16c, and decomposition instead of ligand
coupling may then become a significant competing pathway.
Deprotection of the MOM groups of 17a-c, 18a-c, and 19a,
19b was realized by acid-catalyzed treatment using the HCl-
acetone system, leading to the desired tetracyclic compounds
25a-c, 26a-c, and 27a, 27b, respectively, in a three-step one-
pot cascade sequence of reactions in good overall yields (Table
3). Attempts to deprotect the benzyl fragment in compounds
25a-c, employing Pd/C-H2, Pd/C-HCO2NH4 systems13 or
concentrated HBr18 were unsuccessful.
a Reaction conditions: (i) conc HCl, acetone, 40 °C.
two pairs of substrates 19a, 19b and 20a, 20b may result from
the possibility for compounds 19a, 19b to form, during the acid-
catalyzed hydrolysis, highly reactive p-methylenequinone that
are suitable for cyclization.
One should note that the tetracyclic compounds 25a-c and
26a-c were obtained in higher overall yields than the analogs
27a and 27b containing a phenolic group in the benzopyran
moiety (Table 3). This fact could be explained by a lower
stability of the intermediate 3-[2′-(chloromethyl)-5′-hydroxy-
4′-methoxyphenyl]-4-hydroxycoumarins 23a, 23b in contrast to
coumarins 21a-c and 22a-c that do not exhibit a phenolic
group substituting the B aryl moiety, present on the C-3 position
of the coumarin skeleton (Scheme 5). On the other hand, when
the 3-aryl-4-hydroxycoumarin 19a, precursor of the tetracyclic
product 27a, was treated with dilute HCl (15-20%), the non-
cyclized 3-[2′-(hydroxymethyl)aryl]-4-hydroxycoumarin 29a
was obtained. In the case of 20a and 20b, acid-catalyzed
treatment did not lead to the tetracyclic compounds 28a, 28b
(Table 3). Whatever the conditions, only hydrolysis to the
benzylic alcohol derivative occurred, leading to coumarins 30a
and 30b, respectively. The difference of reactivity between the
These tetracyclic systems can be viewed as rigid analogs of
polymethoxylated natural products, such as colchicine or
(15) (a) Pinhey, J. T. In ComprehensiVe Organometallic Chemistry II;
Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford,
1995; Vol. 11, Chapter 11.11, pp 461-485. (b) Finet, J.-P. In Comprehen-
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Konopelski, J. P. Tetrahedron 2001, 57, 5683. (d) Kano, T.; Saito, S. In
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2002, 38.
(17) (a) Buston, J. E. H.; Compton, R. G.; Leech, M. A.; Moloney, M.
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TABLE 3. Synthesis of Derivatives 25-28
no.
R1
R2
R3
R4
yield (%)
25a
25b
25c
26a
26b
26c
27a
27b
28a
28b
OBn
OBn
OBn
OMe
OMe
OMe
OH
OH
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
OMe
OMe
H
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
H
75
74
53
82
73
64
46
35
(18) Bailly, C.; Bal, C.; Barbier, P.; Combes, S.; Finet, J.-P.; Hildebrand,
M.-P.; Peyrot, V.; Wattez, N. J. Med. Chem. 2003, 46, 5437.
OH
3296 J. Org. Chem., Vol. 72, No. 9, 2007

6H,11H-[2]Benzopyrano-[4,3-c][1]benzopyran-11-ones
TABLE 4. Cytotoxicity of Selected Compounds toward HBL100
Cells
a non-coplanar conformation between A and B aryl rings),
whereas the substitution pattern on the B-ring is more flexible
to structural variations.21 As part of our efforts to discover novel
cytotoxic anticancer chemotherapeutic agents that could act by
inhibition of tubulin polymerization,18.22 we selected some of
our compounds for preliminary biological screening. The
cytotoxicity of these compounds was tested against HBL100
human epithelial mammary cells, and the results are reported
in Table 4. Two compounds showed an interesting cytotoxicity,
compound 26b being slightly more active than compound 30a.
Unfortunately, a number of compounds were not sufficiently
soluble in the assay buffer to allow the evaluation of their
activity. Thus, the preliminary biological screening did not reveal
any new lead compound justifying further developments for
optimizing the biological anti-cancer activity.
Conclusion
The use of MOM-protected o-tolyllead derivatives is an
efficient way to generate dicationic equivalents of polyoxygen-
ated aryllead triacetates, required for the synthesis of highly
oxygenated dibenzo[b,d]pyran derivatives. The presence of a
MOM group in the vicinity of the lead metallic center does not
interfere with the arylating properties of this type of reagents,
which are especially effective for the transfer of highly electron-
rich aryl fragments.11,15 Moreover, the synthesis of polyfunc-
tionalized arylboronic acids of type 10, used for the in situ
generation of the aryllead reagents, can be useful in Suzuki-
Miyaura catalytic transformations23 or in copper-mediated N-,
O, and S-arylation reactions24 for the synthesis of heterocyclic
compounds.
Experimental Section
combretastatin A-4, that inhibit the polymerization of micro-
tubules participating in mitotic spindle formation during cell
division.19
General Methods. All commercially available reagents were
used as received without further purification. All solvents were
purified by standard techniques. Crude materials were purified by
column chromatography (CC) using silicagel 60 (70-230 mesh).
1H NMR and 13C NMR spectra were recorded at 200.13 and 50.32
MHz, respectively. Chemical shifts (δ) are reported in ppm for a
solution of the compound in CDCl3 with SiMe4 as internal reference
unless otherwise stated. J values are given in hertz. 2-Halogenaryl-
benzaldehydes 7a-d12 and 4-benzyloxy-2-iodo-5-methoxybenzyl
alcohol 8a25 were synthesized as previously reported. The 4-hy-
droxycoumarins 15a-c were prepared as previously reported:
4-hydroxy-5,6,7-trimethoxycoumarin 15a,26 4-hydroxy-5,7-dimethox-
ycoumarin 15b27 and 4-hydroxy-6,7-dimethoxycoumarin 15c.16
2-Bromo-4,5-dimethoxybenzyl Alcohol (8b). NaBH4 (0.20 g,
5.2 mmol) was added by small portions to a solution of benzalde-
hyde 7b (2.54 g, 10.4 mmol) in THF (90 mL) and 20% aqueous
(21) (a) Nam, N. H. Curr. Med. Chem. 2003, 10, 1697. (b) Tron, G. C.;
Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. A. J. Med.
Chem. 2006, 49, 3033.
For example, combretastatin A-4, a natural cis-stilbene
isolated from the South African bush willow tree Combretum
caffrum, exhibits a potent cytotoxicity against various cancer
cells, including multi-drug-resistant cell lines.20 Structure-
activity studies have shown that some characteristic structural
features are mandatory for the biological activity (three methoxyl
groups on the A-ring, a cis configuration of the olefin inducing
(22) Rappl, C.; Barbier, P.; Bourgarel-Rey, V.; Gregoire, C.; Gilli, R.;
Carre, M.; Combes, S.; Finet, J.-P.; Peyrot, V. Biochemistry 2006, 45, 9210.
(23) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. (c) Lloyd-Williams, P.; Giralt, E.
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J. Org. Chem, Vol. 72, No. 9, 2007 3297

Naumov et al.
methanol (90 mL). The mixture was stirred for 1 h at room
temperature, then diluted with water (50 mL), and concentrated
under reduced pressure. The aqueous layer was extracted with
AcOEt (4 × 30 mL). The combined organic phases were dried
over anhydrous Na2SO4 and concentrated under reduced pressure,
and the solid residue was recrystallized in AcOEt/hexanes to afford
8b as colorless plates (2.50 g, 97%): mp 141 °C; 1H NMR (200.13
MHz) δ 3.87 (3H, s), 3.88 (3H, s), 4.68 (2H, s), 7.01 (2H, s); 13C
NMR (50.32 MHz) δ 56.1, 56.2, 64.9, 111.9, 112.5, 115.4, 131.8,
148.6, 149.0. Anal. Calcd for C9H11BrO3 (247.09 g mol-1): C,
43.75; H, 4.49. Found: C, 43.66; H, 4.60.
2-Bromo-4-hydroxy-5-methoxybenzyl Alcohol (8c). Prepared
by the same procedure as for 8b. Before the aqueous workup, the
water layer was acidified to pH ∼5. Recrystallization in AcOEt/
hexanes afforded 8c as colorless prismatic crystals (69%): mp 107-
109 °C (dec); 1H NMR (200.13 MHz) δ 3.90 (3H, s), 4.67 (2H, s),
5.62 (1H, s), 6.98 (1H, s), 7.11 (1H, s); 13C NMR (50.32 MHz) δ
56.1, 65.0, 111.3, 113.2, 118.4, 131.2, 145.7, 146.1. Anal. Calcd
for C8H9BrO3 (233.06 g mol-1): C, 41.23; H, 3.89. Found: C,
41.11; H, 3.93.
(1.77 g, 22.0 mmol) in THF (10 mL) was added, and the reaction
was stirred for 5 h at 60 °C and overnight at room temperature.
Then a 10% aqueous solution of Na2CO3 (30 mL) was added to
the reaction mixture, and the organic solvent was removed under
reduced pressure. The residue was dissolved in CH2Cl2 (150 mL)
and washed with water (3 × 30 mL). The organic layer was dried
over Na2SO4, the solvent was distilled under reduced pressure, and
the crude product was purified by CC (eluent AcOEt/hexanes, 3/7)
1
to afford 9c (2.62 g, 38%): mp 70 °C; H NMR (200.13 MHz) δ
3.44 (3H, s), 3.50 (3H, s), 3.88 (3H, s), 4.60 (2H, s), 4.75 (2H, s),
5.20 (2H, s), 7.03 (1H, s), 7.34 (1H, s); 13C NMR (50.32 MHz) δ
55.5, 56.0, 56.3, 68.7, 95.6, 96.1, 112.5, 112.9, 120.2, 131.0, 146.3,
149.1. Anal. Calcd for C12H17BrO5 (321.16 g mol-1): C, 44.88;
H, 5.34. Found: C, 44.66; H, 5.52.
2-Bromo-4-methoxy-5-(methoxymethoxy)-1-(meth-
oxymethoxymethyl)benzene (9d). Prepared under the same reac-
tion conditions as 9c using 5.0 g (21.5 mmol) of 8d, two portions
of NaH (0.94 g of a 60% emulsion in oil, 23.6 mmol), and two
portions of a solution of chloromethoxymethane (1.77 g, 22.0 mmol)
in THF (10 mL). After the usual aqueous workup, the crude product
was purified by CC (eluent AcOEt/hexanes, 3/7) to afford 9d as a
2-Bromo-5-hydroxy-4-methoxybenzyl alcohol (8d). Prepared
by the procedure used for 8c. Recrystallization in AcOEt/hexanes
1
colorless solid (2.48 g, 36%): mp 38-39 °C; H NMR (200.13
1
afforded 8d as grayish prismatic crystals (78%): mp 105 °C; H
MHz) δ 3.42 (3H, s), 3.50 (3H, s), 3.86 (3H, s), 4.57 (2H, s), 4.74
(2H, s), 5.22 (2H, s), 7.06 (1H, s), 7.25 (1H, s); 13C NMR (50.32
MHz) δ 55.5, 56.2, 56.3, 68.7, 95.5, 96.1, 115.2, 115.9, 117.5,
129.4, 145.8, 149.8. Anal. Calcd for C12H17BrO5 (321.16 g mol-1):
C, 44.88; H, 5.34. Found: C, 44.61; H, 5.61.
NMR (200.13 MHz) δ 3.88 (3H, s), 4.64 (2H, s), 5.59 (1H, br. s),
7.00 (1H, s), 7.04 (1H, s); 13C NMR (50.32 MHz) δ 56.3, 64.8,
111.6, 114.9, 115.3, 132.7, 145.1, 146.5. Anal. Calcd for C8H9-
BrO3 (233.06 g mol-1): C, 41.23; H, 3.89. Found: C, 41.16; H,
4.04.
Synthesis of Arylboronic Acids 10a-d. General Procedure.
nBuLi (6.3 mL of a 1.6 M solution in hexanes, 10.1 mmol) was
added dropwise to a solution of 9a (4.0 g, 9.7 mmol) in THF
(50 mL) at -78 °C under an inert gas. The solution was stirred for
10-15 min, and then triisopropyl borate (2.3 mL, 0.01 mmol) was
added. The mixture was stirred at -78 °C for 1.5 h and then warmed
to room temperature overnight. Water (10 mL) was added to the
reaction mixture, and the solvents were distilled under reduced
pressure. AcOEt (80 mL) was added, and the mixture was
vigorously shaken with water (3 × 20 mL) during 5 min. The
organic layer was dried over Na2SO4, and the solvent was distilled
under reduced pressure. The crude product was recrystallized in
AcOEt/hexanes to afford 5-benzyloxy-4-methoxy-2-(meth-
oxymethoxymethyl)phenylboronic acid 10a as a colorless powder
(1.96 g, 61%): mp 105 °C; 1H NMR (200.13 MHz) δ 3.40
(3H, s), 3.90 (3H, s), 4.66 (2H, s), 4.67 (4H, s), 5.18 (2H, s), 6.33
(2H, s), 6.83 (1H, s), 7.33-7.50 (6H, m); 13C NMR (50.32 MHz)
δ 55.9, 56.0, 69.8, 70.9, 94.1, 114.5, 120.9, 127.5, 127.9, 128.5,
134.5, 137.0, 147.6, 150.9. Anal. Calcd for C17H21BO6 (332.16 g
mol-1): C, 61.47; H, 6.37. Found: C, 61.22; H, 6.63.
4,5-Dimethoxy-2-(methoxymethoxymethyl)phenylboronic Acid
(10b). Prepared under the same reaction conditions using 9b
(2.4 g, 8.20 mmol), BuLi (5.6 mL of a 1.6 M solution in hexanes,
9 mmol), and triisopropyl borate (2 mL, 8.6 mmol). The usual
aqueous workup and recrystallization of the crude product in CHCl3/
hexanes afforded 10b as a colorless powder (1.15 g, 55%): mp
126 °C; 1H NMR (200.13 MHz) δ 3.41 (3H, s), 3.91 (3H, s), 3.93
(3H, s), 4.66 (2H, s), 4.68 (2H, s), 6.59 (2H, s), 6.81 (1H, s), 7.41
(1H, s); 13C NMR (50.32 MHz) δ 55.7, 55.8, 55.9, 69.8, 94.0, 113.9,
118.3, 134.0, 148.3, 150.2. Anal. Calcd for C11H17BO6 (256.06 g
mol-1): C, 51.60; H, 6.69. Found: C, 51.55; H, 6.78.
4-Benzyloxy-2-iodo-5-methoxy-1-(methoxymethoxymethyl)-
benzene (9a). Sodium hydride (0.067 g of a 60% emulsion in oil,
1.58 mmol) was added to a cooled (0 °C) solution of 8a25 (0.53 g,
1.43 mmol) in anhydrous THF (15 mL) under argon. The reaction
mixture was stirred for 15 min, and then a solution of chlo-
romethoxymethane (0.12 g, 1.43 mmol) in THF (5 mL) was added.
The reaction mixture was stirred for 2 h at room temperature and
for 3 h at 60 °C. After addition of a 10% aqueous solution of Na2-
CO3 (10 mL), the organic solvent was distilled under reduced
pressure. The residue was dissolved in CH2Cl2 (30 mL) and washed
with water (3 × 7 mL). The organic phase was dried over Na2SO4,
the solvent was distilled under reduced pressure, and the crude
product was purified by CC (eluent ether/hexane, 1/1) to afford 9a
(0.39 g, 65%): mp 75 °C; 1H NMR (200.13 MHz) δ 3.46 (s, 3H),
3.89 (s, 3H), 4.54 (s, 2H), 4.77 (s, 2H), 5.11 (s, 2H), 7.02 (s, 1H),
7.30-7.42 (m, 6H); 13C NMR (50.32 MHz) δ 55.6, 56.0, 71.3,
73.1, 86.0, 96.1, 112.6, 124.2, 127.4, 128.0, 128.6, 133.3, 136.4,
148.2, 150.1. Anal. Calcd for C17H19IO4 (414.23 g mol-1): C, 49.29;
H, 4.62. Found: C, 49.14; H, 4.60.
2-Bromo-4,5-dimethoxy-1-(methoxymethoxymethyl)ben-
zene (9b). Prepared under the same reaction conditions using 8b
(2.50 g, 10.1 mmol), NaH (0.44 g of a 60% emulsion in oil, 11.1
mmol), and chloromethoxymethane (0.89 g, 11.1 mmol). After the
usual aqueous workup the crude product was purified by CC (eluent
ether/hexane, 1/1) to afford 9b as a colorless oil (2.4 g, 81%): 1H
NMR (200.13 MHz) δ 3.40 (3H, s), 3.83 (3H, s), 3.85 (3H, s),
4.57 (2H, s), 4.71 (2H, s), 6.96 (1H, s), 6.97 (1H, s); 13C NMR
(50.32 MHz) δ 55.5, 56.0, 56.2, 68.7, 96.0, 112.3, 113.2, 115.4,
129.2, 148.4, 149.0. Anal. Calcd for C11H15BrO4 (291.14 g mol-1):
C, 45.38; H, 5.19. Found: C, 45.18; H, 5.37.
2-Bromo-5-methoxy-4-(methoxymethoxy)-1-(meth-
oxymethoxymethyl)benzene (9c). Sodium hydride (0.94 g of a
60% emulsion in oil, 23.6 mmol) was added to a cooled (0 °C)
solution of 8c (5.0 g, 21.5 mmol) in anhydrous THF (70 mL) under
argon. After the reaction mixture was stirred for 15 min, a solution
of chloromethoxymethane (1.77 g, 22.0 mmol) in THF (10 mL)
was added. The reaction mixture was stirred for 30 min at room
temperature and 3 h at 60 °C (TLC monitoring) and then cooled to
0 °C, and a second portion of sodium hydride (0.94 g of a 60%
emulsion in oil, 23.6 mmol) was added. After the reaction mixture
was stirred for 15 min, a solution of chloromethoxymethane
4-Methoxy-5-(methoxymethoxy)-2-(methoxymethoxymethyl)-
phenylboronic Acid (10c). Prepared under the same reaction
conditions using 9c (2.4 g, 7.5 mmol), BuLi (5.1 mL of a 1.6 M
solution in hexanes, 8.2 mmol) and triisopropyl borate (1.9 mL,
8.2 mmol). The usual aqueous workup was followed by recrystal-
lization in AcOEt/petroleum ether to afford 10c as a colorless solid
1
(0.81 g, 38%): mp 72-74 °C; H NMR (200.13 MHz) δ 3.41
(3H, s), 3.52 (3H, s), 3.91 (3H, s), 4.66 and 4.67 (2 × 2H, 2 s),
5.27 (2H, s), 6.55 (2H, s), 6.84 (1H, s), 7.64 (1H, s); 13C NMR
(50.32 MHz) δ 55.9, 56.0, 56.3, 69.7, 94.1, 95.3, 114.4, 123.5,
3298 J. Org. Chem., Vol. 72, No. 9, 2007

6H,11H-[2]Benzopyrano-[4,3-c][1]benzopyran-11-ones
135.5, 145.8, 151.0. Anal. Calcd for C12H19BO7 (286.09 g mol-1):
C, 50.38; H, 6.69. Found: C, 50.11; H, 6.74.
Anal. Calcd for C28H28O9 (508.52 g mol-1): C, 66.13; H, 5.55.
Found: C, 66.01; H, 5.78.
5-Methoxy-4-(methoxymethoxy)-2-(methoxymethoxymethyl)-
phenylboronic Acid (10d). Prepared under the same reaction
conditions using 9d (2.2 g, 6.9 mmol), BuLi (4.7 mL of a 1.6 M
solution in hexanes, 7.5 mmol), and triisopropyl borate (1.73 mL,
7.5 mmol). The usual aqueous workup followed by CC of the crude
product (eluent AcOEt/petroleum ether, 1/1) afforded 10d as a
slightly yellow oil that slowly solidified to a colorless powder
(0.81 g, 41%): mp 62-63 °C; 1H NMR (200.13 MHz) δ 3.40 (3H,
s), 3.51 (3H, s), 3.93 (3H, s), 4.66 and 4.67 (2 × 2H, 2 s), 5.26
(2H, s), 6.80 (2H, s), 7.10 (1H, s), 7.45 (1H, s); 13C NMR
(50.32 MHz) δ 55.9 (strong), 56.3, 69.8, 94.3, 95.1, 118.5, 118.9,
133.9, 147.6, 148.9. Anal. Calcd for C12H19BO7 (286,09 g mol-1):
C, 50.38; H, 6.69. Found: C, 50.29; H, 6.83.
3-[5′-Benzyloxy-4′-methoxy-2′-(methoxymethoxymethyl)phe-
nyl]-4-hydroxy-6,7-dimethoxychromen-2-one (17c). CC (AcOEt/
Petroleum ether, 7/3). Yellow crystalline solid (51%): mp 173 °C
1
(dec); H NMR (200.13 MHz) δ 3.27 (3H, s), 3.93 (3H, s), 3.94
(3H, s), 3.97 (3H, s), 4.37 (1H, d, J ) 11.6), 4.52 (1H, d, J )
11.5), 4.62 (1H, d, J ) 6.7), 4.70 (1H, d, J ) 6.7), 5.05 (1H, d, J
) 12.1), 5.15 (1H, d, J ) 12.1), 6.84 (1H, s), 6.86 (1H, s), 7.09
(1H, s), 7.23 (1H, s), 7.30-7.47 (5H, m); 13C NMR (50.32 MHz)
δ 55.8, 56.1, 56.3, 56.4, 68.6, 71.0, 96.6, 99.6, 102.7, 103.7, 107.4,
113.5, 116.6, 121.1, 127.6, 128.0, 128.5, 131.3, 136.5, 146.2, 148.5,
149.1, 150.3, 153.4, 160.9, 162.9. Anal. Calcd for C28H28O9 (508.52
g mol-1): C, 66.13; H, 5.55. Found: C, 65.87; H, 5.85.
3-[4′,5′-Dimethoxy-2′-(methoxymethoxymethyl)phenyl]-4-hy-
droxy-5,6,7-trimethoxychromen-2-one (18a). CC (AcOEt/ Pe-
troleum ether, 1/1). Slightly yellow crystalline solid (78%): mp
132 °C; 1H NMR (200.13 MHz) δ 3.31 (3H, s), 3.86 (3H, s), 3.88
(3H, s), 3.92 (3H, s), 3.95 (3H, s), 4.17 (3H, s), 4.49 (2H, s), 4.62
1,3-Dihydro-6-benzyloxy-1-hydroxy-5-methoxy-2,1-benzox-
aborole (13a). Several drops of concentrated hydrochloric acid were
added to a solution of 10a (0.5 g, 1.5 mmol) in acetone (3 mL).
The mixture was stirred at 40 °C for 1 h (TLC monitoring). The
organic solvent was removed under reduced pressure, and the
residue was dissolved in CHCl3 (10 mL) and washed with water
(3 × 5 mL). The organic layer was dried over Na2SO4, the solvent
was distilled under reduced pressure, and the residue was recrystal-
lized in CHCl3/hexanes to afford 13a as a colorless powder (0.29
(2H, s), 6.71 (1H, s), 6.78 (1H, s), 7.10 (1H, s), 10.01 (1H, s); 13
C
NMR (50.32 MHz) δ 55.2, 55.9, 56.4, 61.4, 62.8, 66.9, 95.6, 96.7,
101.0, 102.9, 111.4, 113.7, 122.1, 130.1, 137.5, 148.2, 148.9, 149.0,
150.3, 157.0, 161.5, 162.3. Anal. Calcd for C23H26O10 (462.45 g
mol-1): C, 59.74; H, 5.67. Found: C, 59.46; H, 5.91.
1
g, 67%): mp 143-144 °C; H NMR (200.13 MHz) δ 3.92 (3H,
3-[4′,5′-Dimethoxy-2′-(methoxymethoxymethyl)phenyl]-4-hy-
droxy-5,7-dimethoxychromen-2-one (18b). CC (AcOEt/petroleum
ether, 1/1). Slightly yellow crystalline solid (62%): mp 140 °C;
1H NMR (200.13 MHz) δ 3.31 (3H, s), 3.85 (3H, s), 3.88 (3H, s),
3.92 (3H, s), 4.01 (3H, s), 4.49 (2H, s), 4.62 (2H, s), 6.38 (1H, d,
J ) 2.0), 6.53 (1H, d, J ) 2.1), 6.77 (1H, s), 7.09 (1H, s), 9.53
(1H, s); 13C NMR (50.32 MHz) δ 55.2, 55.8 (strong), 55.9, 56.9,
66.9, 94.3, 95.5, 95.6, 98.6, 101.9, 111.3, 113.7, 122.2, 130.1, 148.1,
148.8, 155.9, 157.1, 162.0, 162.4, 163.2. Anal. Calcd for C22H24O9
(432.42 g mol-1): C, 61.11; H, 5.59. Found: C, 60.85; H, 5.72.
3-[4′,5′-Dimethoxy-2′-(methoxymethoxymethyl)phenyl]-4-hy-
droxy-6,7-dimethoxychromen-2-one (18c). CC (AcOEt/petroleum
ether, 1/1). Yellow crystalline solid (42%): mp 79-81 °C (dec);
1H NMR (200.13 MHz) δ 3.27 (3H, s), 3.85 (3H, s), 3.92 (3H, s),
3.94 (3H, s), 3.96 (3H, s), 4.38 (1H, d, J ) 11.4), 4.52 (1H, d, J )
11.4), 4.63 (1H, d, J ) 6.8), 4.70 (1H, d, J ) 6.7), 6.76 (1H, s),
6.86 (1H, s), 7.05 (1H, s), 7.25 (1H, s); 13C NMR (50.32 MHz) δ
55.6, 55.9 (strong), 56.3, 56.4, 68.7, 96.6, 99.6, 102.9, 103.8, 107.4,
113.0, 114.2, 121.3, 130.7, 146.2, 149.1, 149.3, 149.6, 153.4, 160.9,
163.0. Anal. Calcd for C22H24O9 (432.42 g mol-1): C, 61.11; H,
5.59. Found: C, 60.92; H, 5.84.
s), 4.60 (1H, s), 5.01 (2H, s), 5.18 (2H, s), 6.86 (1H, s), 7.20 (1H,
s), 7.33-7.45 (5H, m); 13C NMR (50.32 MHz) δ 56.0, 70.9, 71.0,
114.0, 127.2, 127.3, 127.8, 128.5, 137.0, 148.1, 148.4, 153.1. Anal.
Calcd for C15H15BO4 (270.09 g mol-1): C, 66.70; H, 5.60. Found:
C, 66.52; H, 5.82.
1,3-Dihydro-1-hydroxy-4,5-dimethoxy-2,1-benzoxaborole (13b).
Prepared under the same reaction conditions in a 65% yield;
colorless powder: mp 149 °C; 1H NMR (200.13 MHz) δ 3.91 (3H,
s), 3.92 (3H, s), 5.05 (2H, s), 5.35 (1H, br. s), 6.85 (1H, s), 7.19
(1H, s); 13C NMR (50.32 MHz) δ 55.9, 56.0, 70.9, 103.6, 111.3,
147.7, 148.9, 152.4. Anal. Calcd for C9H11BO4 (193.99 g mol-1):
C, 55.72; H, 5.72. Found: C, 55.65; H, 5.93.
Two-Step One-Pot Organolead-Mediated Arylation Reac-
tions. Typical Procedure. A mixture of 10a (0.10 g, 0.30 mmol),
Pb(OAc)4 (0.13 g, 0.3 mmol), and Hg(OAc)2 (0.01 g, 0.03 mmol)
was stirred in anhydrous CHCl3 (1.5 mL) for 1.5 h at 40-45 °C
and for 15 h at room temperature under nitrogen. Pyridine
(0.07 mL, 0.90 mmol) and 4-hydroxy-5,6,7-trimethoxycoumarin 15a
(0.07 g, 0.27 mmol) were added to the reaction mixture, which
was stirred for 10-12 h at 65 °C. The solvent was distilled under
reduced pressure, and the residue was purified by CC (eluent
AcOEt/petroleum ether, 1/1) to afford 3-[5′-benzyloxy-4′-methoxy-
2′-(methoxymethoxymethyl)phenyl]-4-hydroxy-5,6,7-trimethoxy-
chromen-2-one 17a as a colorless polycrystalline solid (0.12 g,
3-[4′-Methoxy-5′-methoxymethoxy-2′-(methoxymethoxymeth-
yl)phenyl]-4-hydroxy-5,6,7-trimethoxychromen-2-one (19a). CC
(AcOEt/petroleum ether, 1/1). Slightly yellow crystalline solid
1
(62%): mp 147-148 °C; H NMR (200.13 MHz) δ 3.32 (3H, s),
1
82%): mp 134-135 °C; H NMR (200.13 MHz) δ 3.32 (3H, s),
3.50 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 3.95 (3H, s), 4.17 (3H, s),
4.50 (2H, s), 4.63 (2H, s), 5.21 (1H, d, J ) 6.7), 5.25 (1H, d, J )
6.7), 6.70 (1H, s), 7.07 (1H, s), 7.14 (1H, s), 9.99 (1H, s); 13C
NMR (50.32 MHz) δ 55.3, 55.9, 56.2, 56.4, 61.4, 62.8, 66.9, 95.6,
95.7, 96.7, 101.1, 102.8, 111.7, 118.7, 122.1, 131.9, 137.5, 145.8,
149.1, 149.6, 150.3, 157.0, 161.6, 162.2. Anal. Calcd for C24H28O11
(492.47 g mol-1): C, 58.53; H, 5.73. Found: C, 58.28; H, 5.96.
3.88 (3H, s), 3.93 (3H, s), 3.95 (3H, s), 4.16 (3H, s), 4.50 (2H, s),
4.63 (2H, s), 5.10 (1H, d, J ) 12.1), 5.15 (1H, d, J ) 12.1), 6.70
(1H, s), 6.85 (1H, s), 7.14 (1H, s), 7.31-7.42 (5H, s), 9.96
(1H, s); 13C NMR (50.32 MHz) δ 55.2, 56.0, 56.4, 61.4, 62.8, 66.9,
71.1, 95.7, 96.7, 101.0, 102.8, 111.9, 116.3, 121.9, 127.5, 127.7,
128.4, 130.7, 137.1, 137.5, 147.6, 149.0, 149.6, 150.3, 157.0, 161.5,
162.3. Anal. Calcd for C29H30O10 (538.54 g mol-1): C, 64.68; H,
5.61. Found: C, 64.51; H, 5.82.
3-[4′-Methoxy-5′-methoxymethoxy-2′-(methoxymethoxymeth-
yl)phenyl]-4-hydroxy-5,7-dimethoxychromen-2-one (19b). CC
(AcOEt/petroleum ether, 2/1). Slightly yellow crystalline solid
(67%): mp 115 °C (dec); 1H NMR (200.13 MHz) δ 3.29 (3H, s),
3.47 (3H, s), 3.85 (3H, s), 3.90 (3H, s), 3.98 (3H, s), 4.48 (2H, s),
4.60 (2H, s), 5.18 (1H, d, J ) 6.6), 5.22 (1H, d, J ) 6.6), 6.35
(1H, d, J ) 2.2), 6.48 (1H, d, J ) 2.2), 7.04 (1H, s), 7.11 (1H, s),
9.51 (1H, s); 13C NMR (50.32 MHz) δ 55.1, 55.7, 55.8, 56.0, 56.9,
66.8, 94.1, 95.4, 95.5, 95.6, 98.5, 101.6, 111.4, 118.7, 122.2, 131.8,
145.5, 149.3, 155.7, 157.0, 162.0, 162.2, 163.1. Anal. Calcd for
C23H26O10 (462,45 g mol-1): C, 59.74; H, 5.67. Found: C, 59.71;
H, 5.89.
3-[5′-Benzyloxy-4′-methoxy-2′-(methoxymethoxymethyl)phe-
nyl]-4-hydroxy-5,7-dimethoxychromen-2-one (17b). CC (AcOEt/
Petroleum ether, 1/1). Colorless crystalline solid (70%): mp
126 °C; 1H NMR (200.13 MHz) δ 3.32 (3H, s), 3.88 (3H, s), 3.92
(3H, s), 4.01 (3H, s), 4.50 (2H, s), 4.63 (2H, s), 5.06 (1H, d, J )
11.8), 5.15 (1H, d, J ) 11.8), 6.38 (1H, d, J ) 2.0), 6.53 (1H, d,
J ) 2.0), 6.85 (1H, s), 7.13 (1H, s), 7.30-7.46 (5H, m), 9.49 (1H,
s); 13C NMR (50.32 MHz) δ 55.2, 55.9, 56.0, 56.9, 67.0, 71.1,
94.3, 95.6, 95.7, 98.7, 101.9, 111.9, 116.4, 122.2, 127.5, 127.7,
128.4, 130.8, 137.2, 147.5, 149.5, 155.9, 157.1, 161.9, 162.3, 163.2.
J. Org. Chem, Vol. 72, No. 9, 2007 3299

Naumov et al.
3-[5′-Methoxy-4′-methoxymethoxy-2′-(methoxymethoxymeth-
yl)phenyl]-4-hydroxy-5,6,7-trimethoxychromen-2-one (20a). CC
(AcOEt/petroleum ether, 1/1). Yellow viscous oil (48%); 1H NMR
(200.13 MHz) δ 3.29 (3H, s), 3.52 (3H, s), 3.87 (3H, s), 3.88
(3H, s), 3.95 (3H, s), 4.17 (3H, s), 4.46 (2H, s), 4.60 (2H, s), 5.27
100.8, 103.5, 107.0, 108.3, 119.4, 119.9, 140.2, 148.6, 149.0, 150.5,
150.7, 156.9, 160.3, 161.6. Anal. Calcd for C21H20O8 (400.38 g
mol-1): C, 63.00; H, 5.03. Found: C, 62.73; H, 5.26.
2,4,8,9-Tetramethoxy-6H,11H-[2]benzopyrano[4,4-c][1]-
benzopyran-11-one (26b). Recrystallization in CHCl3/ether/
petroleum ether. Yellow crystalline solid (73%): mp 178-179 °C;
1H NMR (200.13 MHz) δ 3.84 (3H, s), 3.89 (6H, s), 3.95 (3H, s),
5.24 (2H, s), 6.30 (1H, d, J ) 1.9), 6.44 (1H, d, J ) 1.9), 6.60
(1H, s), 8.13 (1H, s); 13C NMR (50.32 MHz) δ 55.7, 56.0 (strong),
56.3, 69.4, 93.0, 95.9, 99.6, 99.8, 107.0, 108.2, 119.3, 120.2, 148.3,
149.0, 156.1, 158.6, 160.4, 162.9, 163.2. Anal. Calcd for C20H18O7
(370.35 g mol-1): C, 64.86; H, 4.90. Found: C, 64.61; H, 5.18.
2,3,8,9-Tetramethoxy-6H,11H-[2]benzopyrano[4,4-c][1]-
benzopyran-11-one (26c). Recrystallization in CHCl3/ether/
petroleum ether. Yellow crystalline solid (64%): mp 214-216 °C
(2H, s), 6.71 (1H, s), 6.81 (1H, s), 7.36 (1H, s), 10.01 (1H, s); 13
C
NMR (50.32 MHz) δ 55.2, 55.9, 56.2, 56.4, 61.4, 62.8, 66.9, 95.3,
95.6, 96.7, 100.9, 102.9, 114.1, 116.3, 123.8, 130.2, 137.5, 146.5,
148.9, 149.0, 150.3, 157.1, 161.5, 162.3. Anal. Calcd for C24H28O11
(492.47 g mol-1): C, 58.53; H, 5.73. Found: C, 58.27; H, 5.97.
3-[5′-Methoxy-4′-methoxymethoxy-2′-(methoxymethoxymeth-
yl)phenyl]-4-hydroxy-5,7-dimethoxychromen-2-one (20b). CC
(AcOEt/petroleum ether, 1/1). Yellow viscous oil that crystallized
in CHCl3/ether/petroleum ether mixture during 4 days in refrigerator
to afford a slightly yellow solid (45%): mp 134-135 °C; 1H NMR
(200.13 MHz) δ 3.30 (3H, s), 3.53 (3H, s), 3.86 (3H, s), 3.89
(3H, s), 4.02 (3H, s), 4.46 (2H, s), 4.60 (2H, s), 5.28 (2H, s), 6.39
(1H, d, J ) 2.2), 6.54 (1H, d, J ) 2.2), 6.80 (1H, s), 7.36 (1H, s),
9.54 (1H, s); 13C NMR (50.32 MHz) δ 55.2, 55.9, 56.0, 56.2, 57.0,
67.0, 94.3, 95.3, 95.6, 95.7, 98.6, 102.0, 114.2, 116.2, 124.0, 130.3,
146.4, 148.8, 156.0, 157.1, 162.0, 162.4, 163.2. Anal. Calcd for
C23H26O10 (462,45 g mol-1): C, 59.74; H, 5.67. Found: C, 59.61;
H, 5.92.
1
(dec); H NMR (200.13 MHz) δ 3.90 (3H, s), 3.95 (6H, s), 3.97
(3H, s), 5.33 (2H, s), 6.61 (1H, s), 6.82 (1H, s), 7.17 (1H, s), 8.22
(1H, s); 13C NMR (50.32 MHz) δ 56.0, 56.1, 56.3, 56.4, 69.4, 99.5,
100.3, 102.9, 107.2, 107.4, 108.3, 119.3, 119.9, 146.3, 148.5, 148.7,
149.0, 153.3, 160.3, 160.8. Anal. Calcd for C20H18O7 (370.35 g
mol-1): C, 64.86; H, 4.90. Found: C, 64.61; H, 5.18.
Synthesis of Compounds 27a, 27b, 29a, 30a, and 30b. Typical
Procedure. Several drops of concentrated hydrochloric acid were
added to a solution of 19a (0.1 g, 0.20 mmol) in acetone (3 mL).
The mixture was stirred at 40 °C for 1.5 h (TLC monitoring), and
then CHCl3 (15 mL) was added. The mixture was washed with
water (3 × 5 mL), the organic layer was dried over Na2SO4, the
solvent was distilled under reduced pressure, and the residue was
recrystallized in CHCl3/petroleum ether to afford 9-hydroxy-2,3,4,8-
tetramethoxy-6H,11H-[2]benzopyrano[4,4-c][1]benzopyran-11-
one 27a as a yellow crystalline solid (0.036 g, 46%): mp 236-
237 °C; 1H NMR (200.13 MHz) δ 3.88 (3H, s), 3.92 (9H, s), 5.29
(2H, s), 5.81 (1H, s), 6.63 (1H, s), 6.68 (1H, s), 8.15 (1H, s); 13C
NMR (50.32 MHz) δ 56.1, 56.3, 61.4, 62.3, 69.5, 96.3, 100.9, 103.5,
106.6, 111.8, 119.2, 120.5, 140.2, 145.9, 146.3, 150.5, 150.7, 156.9,
160.2, 161.7. Anal. Calcd for C20H18O8 (386,35 g mol-1): C, 62.17;
H, 4.70. Found: C, 61.88; H, 4.96.
9-Hydroxy-2,4,8-trimethoxy-6H,11H-[2]benzopyrano[4,4-c][1]-
benzopyran-11-one (27b). Recrystallization in CHCl3/ether/
petroleum ether. Yellow crystalline solid (35%): mp 253 °C (dec);
1H NMR (200.13 MHz, DMF-d7) δ 3.81 (1H, br. s), 4.02 (3H, s),
4.10 (3H, s), 4.11 (3H, s), 5.48 (2H, s), 6.70 (1H, d, J ) 2.1), 6.76
(1H, d, J ) 2.1), 7.13 (1H, s), 8.15 (1H, s); 13C NMR (50.32 MHz,
DMF-d7) δ 55.9, 56.0, 56.4, 69.1, 93.3, 96.1, 99.3, 99.6, 108.6,
112.1, 119.2, 120.4, 147.0, 147.7, 156.2, 159.2, 159.7, 163.2, 163.9.
Anal. Calcd for C19H16O7 (356.33 g mol-1): C, 64.04; H, 4.53.
Found: C, 63.77; H, 4.75.
Three-Step One-Pot Deprotection-Halogenation-Annula-
tion Sequence for Synthesis of Compounds 25a-c and 26a-c.
Typical Procedure. Several drops of concentrated hydrochloric
acid were added to a solution of 17a (0.1 g, 0.18 mmol) in acetone
(3 mL). The mixture was stirred at 40 °C for 1 h (TLC monitoring).
The organic solvent was removed under reduced pressure, and the
residue was dissolved in CHCl3 (15 mL) and washed with water
(5 mL), 5% aqueous NaOH (2 × 4 mL), 5% aqueous HCl (4 mL),
and water (2 × 5 mL). The organic layer was dried over Na2SO4,
the solvent was distilled under reduced pressure, and the residue
was recrystallized in CHCl3/hexanes to afford 9-benzyloxy-2,3,4,8-
tetramethoxy-6H,11H-[2]benzopyrano[4,4-c][1]benzopyran-11-
one 25a as a slightly yellow powder (0.066 g, 75%): mp 169-
170 °C; 1H NMR (200.13 MHz) δ 3.88 (3H, s), 3.90 (6H, s), 3.92
(3H, s), 5.23 (2H, s), 5.30 (2H, s), 6.65 (1H, s), 6.67 (1H, s), 7.28-
7.40 (3H, m), 7.49-7.55 (2H, m), 8.24 (1H, s); 13C NMR (50.32
MHz) δ 56.2, 56.3, 61.4, 62.3, 69.4, 70.8, 96.3, 100.8, 103.5, 107.6,
110.5, 119.8, 119.9, 127.8, 128.5, 136.9, 140.1, 148.2, 149.2, 150.5,
150.6, 156.8, 160.2, 161.5. Anal. Calcd for C27H24O8
(476.47 g mol-1): C, 68.06; H, 5.08. Found: C, 67.83; H, 5.42.
9-Benzyloxy-2,4,8-trimethoxy-6H,11H-[2]benzopyrano[4,4-c]-
[1]benzopyran-11-one (25b). Recrystallization in CHCl3/
petroleum ether. Yellow crystalline solid (74%): mp 214-216 °C;
1H NMR (200.13 MHz) δ 3.85 (3H, s), 3.87 (6H, s), 5.22 (2H, s),
5.24 (2H, s), 6.30 (1H, d, J ) 1.8), 6.43 (1H, d, J ) 1.8), 6.62
4-Hydroxy-3-[5′-hydroxy-2′-(hydroxymethyl)-4′-methoxyphe-
nyl]-5,6,7-trimethoxychromen-2-one (29a). Synthesized under the
same reaction conditions, except using dilute HCl (15-20%) as
deprotection agent. Recrystallization in CHCl3/petroleum ether.
Slightly yellow crystalline solid (63%): mp 143-144 °C (dec);
1H NMR (200.13 MHz) δ 3.06 (1H, br. s), 3.88 (3H, s), 3.93
(3H, s), 3.95 (3H, s), 4.18 (3H, s), 4.37 (1H, d, J ) 12.1), 4.47
(1H, d, J ) 12.1), 5.69 (1H, s), 6.72 (1H, s), 6.86 (1H, s), 7.09
(1H, s), 10.15 (1H, s); 13C NMR (50.32 MHz) δ 55.9, 56.5, 61.4,
62.9, 63.7, 96.8, 101.0, 102.9, 112.3, 117.0, 122.6, 132.5, 137.7,
145.2, 146.9, 149.0, 150.1, 162.2, 163.7. Anal. Calcd for C20H20O9
(404.37 g mol-1): C, 59.40; H, 4.99. Found: C, 59.25; H, 5.17.
4-Hydroxy-3-[4′-hydroxy-2′-(hydroxymethyl)-5′-methoxyphe-
nyl]-5,6,7-trimethoxychromen-2-one (30a). Recrystallization in
CHCl3/petroleum ether. Slightly yellow crystalline solid (57%): mp
(1H, s), 7.31-7.40 (3H, m), 7.50-7.57 (2H, m), 8.23 (1H, s); 13
C
NMR (50.32 MHz) δ 55.7, 56.2, 56.3, 69.3, 70.9, 93.0, 95.9, 99.6,
99.8, 107.6, 110.4, 119.7, 120.1, 127.8, 127.9, 128.4, 137.0, 148.2,
148.9, 156.1, 158.6, 160.3, 162.8, 163.2. Anal. Calcd for C26H22O7
(446.45 g mol-1): C, 69.95; H, 4.97. Found: C, 69.67; H, 5.19.
9-Benzyloxy-2,3,8-trimethoxy-6H,11H-[2]benzopyrano[4,4-c]-
[1]benzopyran-11-one (25c). Recrystallization in CHCl3/ether/
petroleum ether. Yellow crystalline solid (59%): mp 180-181 °C
1
(dec); H NMR (200.13 MHz) δ 3.90 (3H, s), 3.95 (6H, s), 5.24
(2H, s), 5.33 (2H, s), 6.64 (1H, s), 6.83 (1H, s), 7.18 (1H, s), 7.28-
7.40 (3H, m), 7.49-7.55 (2H, m), 8.32 (1H, s); 13C NMR (50.32
MHz) δ 56.2, 56.3, 56.4, 69.4, 70.9, 99.5, 100.3, 102.9, 107.4,
107.8, 110.4, 119.7, 119.8, 127.8, 127.9, 128.5, 136.9, 146.3, 148.2,
148.7, 149.1, 153.2, 160.2, 160.8. Anal. Calcd for C26H22O7
(446.45 g mol-1): C, 69.95; H, 4.97. Found: C, 69.74; H, 5.16.
2,3,4,8,9-Pentamethoxy-6H,11H-[2]benzopyrano[4,4-c][1]-
benzopyran-11-one (26a). Recrystallization in CHCl3/ether/
petroleum ether. Yellow crystalline solid (82%): mp 172-174 °C;
1H NMR (200.13 MHz) δ 3.88 (3H, s), 3.91 (6H, s), 3.93 (3H, s),
3.97 (3H, s), 5.32 (2H, s), 6.64 (1H, s), 6.69 (2H, s), 8.16 (1H, s);
13C NMR (50.32 MHz) δ 56.0, 56.1, 56.3, 61.4, 62.3, 69.5, 96.3,
1
121-123 °C (dec); H NMR (200.13 MHz) δ 2.15 (1H, br. s),
3.89 (6H, s), 3.96 (3H, s), 4.18 (3H, s), 4.47 (2H, s), 5.71 (1H,
br. s), 6.73 (1H, s), 6.77 (1H, s), 7.10 (1H, s), 10.10 (1H, s); 13C
NMR (50.32 MHz) δ 44.7, 56.0, 56.5, 61.4, 62.9, 96.8, 100.9, 102.4,
113.5, 116.1, 122.5, 130.2, 137.5, 145.7, 146.6, 149.1, 150.4, 157.2,
162.2, 162.4. Anal. Calcd for C20H20O9 (404.37 g mol-1): C, 59.40;
H, 4.99. Found: C, 59.13; H, 5.21.
3300 J. Org. Chem., Vol. 72, No. 9, 2007

6H,11H-[2]Benzopyrano-[4,3-c][1]benzopyran-11-ones
4-Hydroxy-3-[4′-hydroxy-2′-(hydroxymethyl)-5′-methoxyphe-
nyl]-5,7-dimethoxychromen-2-one (30b). Recrystallization in
CHCl3/petroleum ether. Slightly yellow crystalline solid (44%): mp
Cytotoxicity Tests. The HBL100 cells were seeded in 96-well
plates to be treated during 72 h. The compounds were dissolved in
DMSO at a 10 mM concentration and diluted in the tissue culture
medium before use. The number of viable cells were estimated by
using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltet-
razolium bromide (MTT; Sigma) assay, and absorbance was
measured at 550 nm with a Dynatech MR 7-000 plate reader. At
least three independent experiments were performed for each
compound, and the IC50 values (i.e., concentration half-inhibiting
cell proliferation) were graphically determined.
1
127 °C (dec); H NMR (200.13 MHz) δ 1.96 (1H, br. s), 3.87
(3H, s), 3.89 (3H, s), 4.03 (3H, s), 4.48 (2H, s), 5.68 (1H, br. s),
6.39 (1H, d, J ) 2.0), 6.55 (1H, d, J ) 2.0), 6.76 (1H, s), 7.10
(1H, s), 9.61 (1H, s); 13C NMR (50.32 MHz) δ 44.7, 55.9, 56.0,
57.0, 94.3, 95.7, 98.6, 101.6, 113.5, 116.0, 122.7, 130.3, 145.6,
146.6, 156.0, 157.2, 162.5, 162.6, 163.4. Anal. Calcd for C19H18O8
(374.34 g mol-1): C, 60.96; H, 4.85. Found: C, 60.72; H, 5.07.
Acknowledgment. This work was supported by INTAS
(grant no. 03-514915), Russian Foundation for Basic Research
(grant no. 06-03-32772), and Russian Federal Special Purpose
Program (grant no. 2007-3-1.3-22-01-584). O.G. thanks INTAS
for a YS-05-109-5412 fellowship. Yu. N. Novotorov is thanked
for a generous gift of stabilizator-free Pb(OAc)4. We thank also
Dr. Pascale Barbier and Pr. Vincent Peyrot (CISMET, Faculte´
de Pharmacie de Marseille) for fruitful discussions.
Cell Culture. Human epithelial mammary HBL100 cells were
grown in Dulbecco’s modified Eagle’s medium (DMEM, Gibco)
supplemented with 10% foetal bovine serum (FBS), 2 mM
l-glutamine, and 1% penicillin/streptomycin (Gibco) and maintained
in a humidified incubator at 37 °C with 5% CO2. For cytotoxicity
experiments, exponentially growing cell cultures (2.6 × 104 cells/
cm2) were trypsinized with 0.25% trypsin/2 mM EDTA and seeded
24 h before treatment with the drug.
JO062592V
J. Org. Chem, Vol. 72, No. 9, 2007 3301