Synthesis of 4-(2-hydroxymethylaryl)coumarins

Article abstract of DOI:10.1007/s11172-010-0130-3

New 4-(2-hydroxymethylaryl)coumarins were prepared using the Suzuki-Miyaura cross- coupling at the key step. According to X-ray diffraction data, the compounds obtained are structural analogs of the natural stilbene combretastatin A-4, which exhibits potent antitumor activity.

Full text of DOI:10.1007/s11172-010-0130-3

Russian Chemical Bulletin, International Edition, Vol. 59, No. 3, pp. 626—631, March, 2010
626
Synthesis of 4ꢀ(2ꢀhydroxymethylaryl)coumarins
N. S. Sitnikov,a A. S. Shavyrin,b G. K. Fukin,b I. P. Beletskaya,c S. Combes,d and A. Yu. Fedorova
aN. I. Lobachevsky Nizhny Novgorod State University,
23 prosp. Gagarina, 603950 Nizhny Novgorod, Russian Federation.
Fax: +7 (831) 462 3085. Eꢀmail: afnn@rambler.ru
bG. A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences,
49 ul. Tropinina, 603600 Nizhny Novgorod, Russian Federation.
Fax: +7 (831) 462 7497. Eꢀmail: andrew@imoc.sinn.ru
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3618. Eꢀmail: beletska@org.chem.msu.ru
dUMRꢀCNRS 6264, Saint Jérome Department of Sciences, AixꢀMarseille University 1 and 2,
case 521, 13397 Marseille, Cedex 20, France.
Fax: +33 (0) 4 91 28 8758. Eꢀmail: Sebastien.Combes@univꢀprovence.fr
New 4ꢀ(2ꢀhydroxymethylaryl)coumarins were prepared using the Suzuki—Miyaura crossꢀ
coupling at the key step. According to Xꢀray diffraction data, the compounds obtained are
structural analogs of the natural stilbene combretastatin Aꢀ4, which exhibits potent antitumor
activity.
Key words: 4ꢀtrifluoromethylsulfonyloxycoumarins, arylboronic acids, 4ꢀ(2ꢀhydroxyꢀ
methylaryl)coumarins, the Suzuki—Miyaura crossꢀcoupling, antitumor activity.
4ꢀArylcoumarins 1 are natural compounds isolated
isolated from Streptomyces aureofaciens is highly active
against tumor growth.3 Its synthetic analogs 1b and 1c
containing a similar set of substituents in the aromatic
rings A and C can also efficiently prevent the formation of
the mitotic spindle in a tumor cell by inhibiting the polyꢀ
merization of the protein tubulin.4 The higher antitumor
activity of combretastatin Aꢀ4 compared to compounds
1b and 1c is due to the fact that hydrogen bonding between
from the plants of the families Guttiferae, Rubiaceae, Leꢀ
guminosae, Passifloraceae, and Compositae.1 The presence
of two nonꢀcoplanar synꢀaryl fragments A and C linked by
a rigid C—C bond makes these compounds structurally
similar to combretastatin Aꢀ4 (cisꢀstilbene isolated from
the African plant Combretum cafrum that exhibits potent
antimitotic activity2). Indeed, neoflavonoid 1a recently
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 612—617, March, 2010.
1066ꢀ5285/10/5903ꢀ0626 © 2010 Springer Science+Business Media, Inc.

4ꢀ(2ꢀHydroxymethylaryl)coumarins
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
627
Scheme 1
MOM = CH2OMe
Reagents and conditions: Pd(dppf)Cl2 (5 mol.%)
K3PO4 (3 equiv.), Bu4NBr (0.1 equiv.), MeCN, 3 h, 80 °C.
Comꢀ
pound
7a
7b
7c
8a
8b
8c
R1
R2
R3
R4
R5
Yield
(%)
93
98
97
91
95
97
H
H
H
OMe
H
H
OMe
H
OMOM
OMOM
OMOM
OMe
OMe
OMe
OMe
OMe
OMe
OMOM
OMOM
OMOM
Comꢀ
pound
6a
6b
6c
R1
R2
R3
R4
R5
Yield
(%)
91
97
91
OMe
OMe
H
OMe
OMe
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
H
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
the fragment of the peptide chain of the protein tubulin
Thr179 and the ring B of combretastatin Aꢀ4 is thermodyꢀ
namically more favorable than hydrogen bonding between
the same protein fragment and ring C of compounds 1b
and 1c (see Ref. 5).
The protecting methoxymethyl groups in compounds
6—8 were removed under the action of HCl in aceꢀ
tone (Scheme 2). The yields of derivatives 9—11 were
53—88%.
A serious drawback of combretastatin Aꢀ4 is its high
tendency toward Z—E isomerization, which substantially
deteriorates its antitumor activity on storage and applicaꢀ
tion of combretastatinꢀbased drugs.2,6 In a search for
novel neoflavonoid analogs of combretastatin Aꢀ4 with
high antitumor activity, we synthesized new 4ꢀarylcouꢀ
marins 2 containing the 2ꢀhydroxymethyl substituent
in the aryl fragment. Earlier,7 antitumor activity have
been found in isoflavonoid 3 containing a substituted aryl
fragment in position 3. Compound 3 can be regarded as
a structural analog of the soybean isoflavones genistein
and daidzein.8
The key step in the synthesis of 4ꢀarylcoumarins 2 is
the Suzuki—Miyaura crossꢀcoupling9 between polymethꢀ
oxycoumarin triflates 4a—c (see Refs 4, 10) and appropriꢀ
ate arylboronic acids 5a—c (see Ref. 7) containing a methꢀ
oxymethylꢀprotected OH group (Scheme 1). The prepaꢀ
ration of compounds 6—8 was complicated by a synthetic
problem to be solved, namely, introduction of electronꢀ
rich aromatic fragments into the coumarin substrate alꢀ
ready containing the electronꢀdonating methoxy groups.
The problem arises from hindered oxidative addition
stage in the catalytic cycle.9 However, the use of the caꢀ
talytic system Pd(dppf)Cl2 (5 mol.%)—K3PO4 (3 equiv.)—
Bu4NBr (0.1 equiv.)11 allowed the synthesis of the target
products in 91—98% yields, regardless of the number of
methoxy groups in the coumarin moiety and the structure
of an arylboronic acid (Scheme 1).
Scheme 2
Comꢀ
pound
9a
9b
9c
10a
10b
10c
11a
11b
11c
R1
R2
R3
R4
R5
Yield
(%)
65
67
62
60
86
82
62
H
H
H
OMe
H
H
OMe
H
H
OMe
OMe
OMe
OMOM
OMOM
OMOM
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
OMe
H
OMe
OMOM
OMOM
OMOM
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
88
53
Reagents and conditions: HCl, acetone, 40 °C.
It should be noted that this reaction yields the correꢀ
sponding 4ꢀ(2ꢀchloromethylaryl)coumarins as byꢀproducts.
For instance, removal of the methoxymethyl protection
from compound 7a resulted in the formation of benzylic
chloride 12 in 25% yield, obviously, through an interacꢀ

628
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Sitnikov et al.
Table 1. Selected crystallographic parameters and the data
collection and refinement statistics for compound 9c
tion of HCl with the hydroxy group of benzylic alcohol
10a (Scheme 3). When heated to 50 °C in water—acetone
(1 : 2), chloride 12 is easily transformed into alcohol 10a.
Parameter
9c
Molecular formula
C21H22O8
402.39
Scheme 3
Molecular mass
Space group
a/Å
b/Å
c/Å
α/deg
β/deg
P1
8.6726(3)
10.0670(3)
12.4691(4)
113.000(1)
101.746(1)
93.022(1)
970.49(5)
γ/deg
3
V/Å
Z
2
dcalc/g cm–3
μ/mm–1
1.377
0.106
Conditions: i. HCl, acetone, 40 °C; ii. H2O, acetone, 50 °C.
F(000)
424
2θmax/deg
Number of independent reflections
56
4664
(0.0137)
0.0383
0.1117
0.379/–0.268
Analysis of structure—antitumor activity correlations
for combretastatin Aꢀ4 and its analogs showed that the
activity is exhibited only by those derivatives in which the
distance between rings A and B is in fine balance with their
relative spatial orientations.12 The structure of compound
9c was ultimately determined by Xꢀray diffraction (Fig. 1,
Table 1). The aromatic rings in this derivative are not
coplanar. The dihedral angle between the planes of the
aromatic fragments A and C in compound 9c is 63.7°,
which is larger than that between rings A and B in comꢀ
bretastatin Aꢀ4 (53.0°) (see Refs 11, 13).
The distance between the center of ring A in comꢀ
pound 9c and the methyl C atom in substituent R4 (C(20)
atom) is 8.52 Å, while an analogous distance in combretꢀ
astatin is 8.59 Å (see Ref. 13). The distance between the
centers of rings A and C in neoflavonoid 9c and between
the centers of the aromatic fragments A and B in comꢀ
bretastatin Aꢀ4 are also nearly equal (5.21 and 5.24 Å,
respectively).
(Rint
)
R1 (on F for reflections with I > 2σ(I))
wR2 (on F2 for all reflections)
Residual electron density peaks,
max/min, e/Å
3
Experimental
1
H and 13C NMR spectra were recorded on a Bruker ARX
400 spectrometer (300.13 and 75.54 MHz, respectively) in
CDCl3. Chemical shifts (δ) are referenced to Me4Si. Elemental
analysis was carried out on a PerkinꢀElmer Series II CHN/O
Analysis 2400 instrument. Commercial reagents (AlfaAesar,
Aldrich) Pd(dppf)Cl2, Bu4NBr, AcCl, a dispersion of NaH in
mineral oil, chloro(methoxy)methane, NaBH4, BuLi, and
(PriO)3B were used as purchased. Solvents were purified acꢀ
cording to standard procedures. Light petroleum with b.p.
40—70 °C was employed. Arylboronic acids 5a—c and coumarin
trifluoromethanesulfonates 4a—c were prepared as described
earlier.4,7
Because of a considerable structural similarity between
flavonoid 9c and combretastatin Aꢀ4, one can expect that
some of compounds 9—11 will show antitumor activity.
Compounds 9—11 are being tested in vitro for cytoꢀ
toxic activity.
Xꢀray diffraction was carried out on a Smart APEX automatꢀ
ic diffractometer (graphite monochromator, MoꢀKα, ϕꢀω scan
mode) at 100 K. The structure was solved by the direct methods
and refined by the leastꢀsquares method on F 2hkl in the anisotropic
approximation for all nonꢀhydrogen atoms with the SHELXTL
program.14 The H atoms in compound 9c were located from
difference electronꢀdensity maps and refined isotropically. Seꢀ
lected crystallographic parameters and the data collection and
refinement statistics are given in Table 1.
Synthesis of compounds 6—8 (general procedure). 4ꢀTrifluoroꢀ
methylsulfonyloxycoumarin (1 equiv., 0.3 mmol), an arylboronꢀ
ic acid (1.3 equiv.), K3PO4 (3 equiv.), Bu4NBr (0.1 equiv.), and
Pd(dppf)Cl2 (0.05 equiv.) were placed in freshly distilled MeCN
(3 mL) under argon. The reaction mixture was stirred at 80 °C
for 3 h. The solvent was removed under reduced pressure and the
product was isolated by column chromatography on silica gel.
4ꢀ[4,5ꢀDimethoxyꢀ2ꢀ(methoxymethoxymethyl)phenyl]chroꢀ
menꢀ2ꢀone (6a) was obtained from 4ꢀtrifluoromethylsulfonylꢀ
O(6)
O(1)
C(14)
C(9)
C(15)
C(19)
C(8)
C(20)
O(7)
O(8)
C(16)
C(1)
O(2)
C(2)
C(3)
C(4)
C
C(13)
C(7)
C(17)
C(18)
C(21)
C(6)
A
O(5)
C(10)
C(11)
C(5)
O(4)
C(12)
O(3)
Fig. 1. Molecular structure 9c.

4ꢀ(2ꢀHydroxymethylaryl)coumarins
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
629
oxycoumarin (4a) and arylboronic acid 5a. The eluent for colꢀ
umn chromatography was AcOEt—light petroleum (2 : 3). Yield
91%, beige needleꢀlike crystals, m.p. 129—130 °C. Found (%):
C, 67.20; H, 5.64. C20H20O6. Calculated (%): C, 67.41; H, 5.66.
1H NMR (CDCl3), δ: 3.23 (s, 3 H, CH2OMe); 3.86 and 3.97
(both s, 3 H each, OMe); 4.33 (s, 2 H, ArCH2); 4.50 (s, 2 H,
OCH2O); 6.39, 6.71, and 7.10 (all s, 1 H each, HC(3), HC(3´),
HC(6´)); 7.17 (m, 2 H, HC(6), HC(8)); 7.39 (d, 1 H, HC(5),
J = 8.1 Hz); 7.53 (m, 1 H, HC(7)). 13C NMR (CDCl3), δ: 55.3;
56.0; 56.1; 66.8; 96.0; 111.5; 112.3; 116.3; 117.1; 119.9; 124.3;
126.4; 127.0; 128.1; 132.0; 148.5; 149.6; 153.7; 154.6; 160.5.
4ꢀ[4,5ꢀDimethoxyꢀ2ꢀ(methoxymethoxymethyl)phenyl]ꢀ5,7ꢀ
dimethoxychromenꢀ2ꢀone (6b) was obtained from 5,7ꢀdimethoxyꢀ
4ꢀtrifluoromethylsulfonyloxycoumarin (4b) and arylboronic acid
5a. The eluent for column chromatography was AcOEt—light
petroleum (1 : 1). Yield 97%, colorless crystals, m.p. 94—96 °C.
Found (%): C, 63.28; H, 5.77. C22H24O8. Calculated (%): C,
(s, 2 H, CH2OCH2O); 5.26 and 5.29 (both d, 1 H each, OCHAHBO,
OCHAHBO, J = 5.1 Hz); 6.01 (s, 1 H, HC(3)); 6.19 (d, 1 H,
HC(6), J = 1.8 Hz); 6.51 (d, 1 H, HC(8), J = 1.8 Hz); 6.65 and
7.24 (both s, 1 H each, HC(3´), HC(6´)). 13C NMR (CDCl3), δ:
55.2; 55.72; 55.75; 56.1; 56.3; 66.8; 93.5; 95.6 (intense peak);
95.8; 104.0; 111.1; 112.8; 116.4; 127.0; 133.2; 145.8; 148.6; 153.9;
156.8; 158.2; 160.7; 163.4.
5,6,7ꢀTrimethoxyꢀ4ꢀ[5ꢀmethoxyꢀ4ꢀmethoxymethoxyꢀ2ꢀ(methꢀ
oxymethoxymethyl)phenyl]chromenꢀ2ꢀone (7c) was obtained from
5,6,7ꢀtrimethoxyꢀ4ꢀtrifluoromethylsulfonyloxycoumarin (4c)
and arylboronic acid 5b. The eluent for column chromatography
was AcOEt—light petroleum (1 : 1). Yield 97%, white needleꢀ
like crystals, m.p. 104—105 °C. Found (%): C, 60.39; H, 5.87.
C24H28O10. Calculated (%): C, 60.50; H, 5.92. 1H NMR (CDCl3),
δ: 3.24 (s, 3 H, CH2OMe); 3.28 (s, 3 H, OMe); 3.55 (s, 3 H,
CH2OMe); 3.75, 3.86, and 3.93 (all s, 3 H each, OMe); 4.31 and
4.35 (both d, 1 H each, ArCHAHB, ArCHAHB, J = 5.1 Hz); 4.52
and 4.55 (both d, 1 H each, CH2OCHAHBO, CH2OCHAHBO,
J = 5.1 Hz); 5.27 and 5.30 (both d, 1 H each, OCHAHBO,
OCHAHBO, J = 5.1 Hz); 6.08 (s, 1 H, HC(3)); 6.70, 6.72, and
7.28 (all s, 1 H each, HC(8), HC(3´), HC(6´)). 13C NMR
(CDCl3), δ: 55.2; 56.1; 56.2; 56.3 (intense peak); 60.9; 61.0;
66.0; 95.6; 95.9; 96.2; 107.7; 111.2; 114.3; 116.4; 127.3; 132.4;
139.3; 146.0; 148.4; 151.0; 153.6; 156.9; 160.5.
4ꢀ[4ꢀMethoxyꢀ5ꢀmethoxymethoxyꢀ2ꢀ(methoxymethoxyꢀ
methyl)phenyl]chromenꢀ2ꢀone (8a) was obtained from 4ꢀtrifluoꢀ
romethylsulfonyloxycoumarin (4a) and arylboronic acid 5c. The
eluent for column chromatography was AcOEt—light petroleum
(2 : 3). Yield 91%, yellow crystals, m.p. 80—81 °C. Found (%):
C, 65.39; H, 5.77. C21H22O7. Calculated (%): C, 65.28; H, 5.74.
1H NMR (CDCl3), δ: 3.23 and 3.49 (both s, 3 H each, CH2OMe);
3.98 (s, 3 H, OMe); 4.33 (s, 2 H, ArCH2); 4.54 (s, 2 H,
CH2OCH2O); 5.22 (s, 2 H, OCH2O); 6.37 and 7.03 (both s,
1 H each, HC(3), HC(3´)); 7.16 (m, 3 H, HC(6´), HC(6),
HC(8)); 7.38 (d, 1 H, HC(5), J = 11.7 Hz); 7.53 (m, 1 H,
HC(7)). 13C NMR (CDCl3), δ: 55.4; 56.0; 56.3; 66.8; 95.6; 96.0;
112.7; 116.4; 116.8; 117.1; 119.8; 124.2; 126.4; 127.0; 129.8;
131.9; 146.0; 150.4; 153.7; 154.2; 160.5.
1
63.45; H, 5.81. H NMR (CDCl3), δ: 3.26 (s, 3 H, CH2OMe);
3.39, 3.84, 3.86, and 3.95 (all s, 3 H each, OMe); 4.32 (s, 2 H,
ArCH2); 4.54 (s, 2 H, OCH2O); 5.99 (s, 1 H, HC(3)); 6.19 (d, 1 H,
HC(6), J = 2.0 Hz); 6.51 (d, 1 H, HC(8), J = 2.0 Hz); 6.62 and
6.99 (both s, 1 H each, HC(3´), HC(6´)). 13C NMR (CDCl3), δ:
55.2; 55.71; 55.74; 55.9; 56.0; 66.8; 93.5; 95.6; 95.7; 104.1; 110.6;
111.0; 113.0; 126.7; 131.4; 147.7; 148.4; 154.0; 156.9; 158.2;
160.7; 163.4.
4ꢀ[4,5ꢀDimethoxyꢀ2ꢀ(methoxymethoxymethyl)phenyl]ꢀ5,6,7ꢀ
trimethoxychromenꢀ2ꢀone (6c) was obtained from 5,6,7ꢀtriꢀ
methoxyꢀ4ꢀtrifluoromethylsulfonyloxycoumarin (4c) and arylꢀ
boronic acid 5a. The eluent for column chromatography was
AcOEt—light petroleum (2 : 3). Yield 91%, beige crystals, m.p.
108—109 °C. Found (%): C, 62.99; H, 5.90. C23H26O9. Calcuꢀ
lated (%): C, 62.88; H, 5.87. 1H NMR (CDCl3), δ: 3.25 (s, 3 H,
CH2OMe); 3.27, 3.75, 3.86, 3.91, and 3.94 (all s, 3 H each,
OMe); 4.35 (s, 2 H, ArCH2); 4.56 (s, 2 H, OCH2O); 6.07, 6.68,
6.71, and 7.03 (all s, 1 H each, HC(3), HC(8), HC(3´), HC(6´)).
13C NMR (CDCl3), δ: 55.3; 56.0; 56.1; 56.2; 60.9; 61.0; 67.0;
95.9; 96.2; 107.8; 110.8; 111.2; 114.4; 127.1; 130.6; 139.4; 147.6;
148.5; 151.0; 151.4; 153.7; 156.9; 160.5.
4ꢀ[5ꢀMethoxyꢀ4ꢀmethoxymethoxyꢀ2ꢀ(methoxymethoxyꢀ
methyl)phenyl]chromenꢀ2ꢀone (7a) was obtained from 4ꢀtrifluoꢀ
romethylsulfonyloxycoumarin (4a) and arylboronic acid 5b. The
eluent for column chromatography was AcOEt—light petroleum
(1 : 2). Yield 93%, colorless crystals, m.p. 72—73 °C. Found (%):
C, 65.44; H, 5.75. C21H22O7. Calculated (%): C, 65.28; H, 5.74.
1H NMR (CDCl3), δ: 3.21 and 3.57 (both s, 3 H each, CH2OMe);
3.86 (s, 3 H, OMe); 4.30 (s, 2 H, ArCH2); 4.51 (s, 2 H,
CH2OCH2O); 5.32 (s, 2 H, OCH2O); 6.38 and 7.03 (both s,
1 H each, HC(3), HC(3´)); 7.17 (m, 3 H, HC(6´), HC(6),
HC(8)); 7.39 (d, 1 H, HC(5), J = 11.7 Hz); 7.53 (m, 1 H,
HC(7)). 13C NMR (CDCl3), δ: 55.3; 56.1; 56.4; 66.8; 95.4; 96.0;
112.1; 116.3; 117.0; 117.4; 119.8; 124.2; 127.1; 128.1; 128.2;
132.0; 147.2; 149.3; 153.7; 154.5; 160.5.
5,7ꢀDimethoxyꢀ4ꢀ[5ꢀmethoxyꢀ4ꢀmethoxymethoxyꢀ2ꢀ(methꢀ
oxymethoxymethyl)phenyl]chromenꢀ2ꢀone (7b) was obtained from
5,7ꢀdimethoxyꢀ4ꢀtrifluoromethylsulfonyloxycoumarin (4b) and
arylboronic acid 5b. The eluent for column chromatography was
AcOEt—light petroleum (1 : 1). Yield 98%, pink powdery solid,
m.p. 99 °C. Found (%): C, 61.73; H, 5.87. C23H26O9. Calculatꢀ
ed (%): C, 61.88; H, 5.87. 1H NMR (CDCl3), δ: 3.24 (s, 3 H,
CH2OMe); 3.39 (s, 3 H, OMe); 3.55 (s, 3 H, CH2OCH3); 3.83
and 3.86 (both s, 3 H each, OMe); 4.29 (s, 2 H, ArCH2); 4.51
5,7ꢀDimethoxyꢀ4ꢀ[4ꢀmethoxyꢀ5ꢀmethoxymethoxyꢀ2ꢀ(methꢀ
oxymethoxymethyl)phenyl]chromenꢀ2ꢀone (8b) was obtained from
5,7ꢀdimethoxyꢀ4ꢀtrifluoromethylsulfonyloxycoumarin (4b) and
arylboronic acid 5c. The eluent for column chromatography was
AcOEt—light petroleum (1 : 1). Yield 95%, colorless powdery
solid, m.p. 133 °C. Found (%): C, 61.96; H, 5.88. C23H28O9.
Calculated (%): C, 61.88; H, 5.87. 1H NMR (CDCl3), δ: 3.27
(s, 3 H, CH2OMe); 3.40 (s, 3 H, OMe); 3.49 (s, 3 H, CH2OMe);
3.86 and 3.94 (both s, 3 H each, OMe); 4,33 (s, 2 H, ArCH2);
4.54 (s, 2 H, CH2OCH2O); 5.19 (s, 2 H, OCH2O); 5.99 (s, 1 H,
HC(3)); 6.18 and 6.51 (both d, 1 H each, HC(6), HC(8),
J = 1.8 Hz); 6.91 and 7.02 (both s, 1 H each, HC(3´), HC(6´)).
13C NMR (CDCl3), δ: 55.3; 55.7; 55.75; 56.0; 56.2; 66.8; 93.6;
95.7 (intense peak); 95.8; 104.1; 111.4; 113.0; 115.9; 128.6; 131.5;
145.2; 149.2; 153.6; 156.9; 158.3; 160.7; 163.4.
5,6,7ꢀTrimethoxyꢀ4ꢀ[4ꢀmethoxyꢀ5ꢀmethoxymethoxyꢀ2ꢀ(methꢀ
oxymethoxymethyl)phenyl]chromenꢀ2ꢀone (8c) was obtained from
5,6,7ꢀtrimethoxyꢀ4ꢀtrifluoromethylsulfonyloxycoumarin (4c)
and arylboronic acid 5c. The eluent for column chromatography
was AcOEt—light petroleum (1 : 1). Yield 97%, colorless crysꢀ
tals, m.p. 72—73 °C. Found (%): C, 60.39; H, 5.90. C24H28O10
.
Calculated (%): C, 60.50; H, 5.92. 1H NMR (CDCl3), δ: 3.26
(s, 3 H, CH2OMe); 3.28 (s, 3 H, OMe); 3.47 (s, 3 H, CH2OMe);

630
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
Sitnikov et al.
3.75, 3.93, and 3.95 (all s, 3 H each, OMe); 4.37 (s, 2 H, ArCH2);
4.57 (s, 2 H, OCH2O); 5.19 and 5.22 (both d, 1 H each, OCHAHBO,
OCHAHBO, J = 5.1 Hz); 6.06, 6.70, 6.97, and 7.06 (all s,
1 H each, HC(3), HC(8), HC(3´), HC(6´)). 13C NMR (CDCl3),
δ: 55.3; 56.0; 56.1; 56.3; 60.9; 61.0; 67.0; 95.6; 95.9; 96.2; 107.8;
111.5; 114.4; 115.8; 129.0; 130.6; 139.4; 144.9; 149.3; 151.0;
151.4; 153.4; 156.9; 160.5.
C, 68.45; H, 4.73. 1H NMR (CDCl3), δ: 3.88 (s, 3 H, OMe);
4.39 and 4.42 (both d, 1 H each, CHAHB, CHAHB, J = 8.2 Hz);
5.91 (s, 1 H, ArOH); 6.37 and 6.70 (both s, 1 H each, HC(3),
HC(3´)); 7.17 (m, 3 H, HC(6´), HC(6), HC(8)); 7.39 (d, 1 H,
HC(5), J = 7.8 Hz); 7.53 (m, 1 H, HC(7)). 13C NMR (CDCl3),
δ: 56.2; 62.2; 111.1; 115.0; 116.3; 117.2; 119.9; 124.4; 125.2;
126.9; 131.7; 132.1; 146.1; 146.6; 153.7; 154.8; 160.7.
Synthesis of compounds 9—11 (general procedure). The startꢀ
ing substrate (~100 mg) was dissolved in distilled acetone (2 mL).
Five to six drops of 15% HCl were added and the mixture was
stirred at 40 °C for 1 h. Then 3—4 drops of conc. HCl were added
and stirring was continued at 40 °C until the starting compound
was completely consumed (TLC). The reaction mixture was diꢀ
luted with water until the solution became slightly turbid (~1 mL)
and stirred at 50 °C for ~30 min until the byꢀproduct benzylic
chloride disappeared (TLC). The solvent was removed under
reduced pressure. The residue was diluted with ethyl acetate
(30 mL) and washed with a saturated solution of NaHCO3
(3×7 mL). The organic layer was dried over anhydrous Na2SO4.
The solvent was removed under reduced pressure. The product
was isolated by column chromatography on silica gel.
4ꢀ(2ꢀHydroxymethylꢀ4,5ꢀdimethoxyphenyl)chromenꢀ2ꢀone
(9a) was obtained from compound 6a. The eluent for column
chromatography was AcOEt—light petroleum (1 : 1). Yield 65%,
colorless polycrystalline powder, m.p. 177—178 °C. Found (%):
C, 69.29; H, 5.17. C18H16O5. Calculated (%): C, 69.22; H, 5.16.
1H NMR (CDCl3), δ: 3.87 and 3.98 (both s, 3 H each, OMe);
4.46 (s, 2 H, CH2); 6.36 (s, 1 H, HC(3)); 6.71 (s, 1 H, HC(3´));
7.18 (m, 3 H, HC(6´), HC(6), HC(8)); 7.39 (d, 1 H, HC(5),
J = 8.0 Hz); 7.54 (m, 1 H, HC(7)). 13C NMR (CDCl3), δ: 56.0;
56.1; 62.3; 111.4; 111.6; 116.3; 117.2; 119.9; 124.4; 125.5; 126.9;
130.9; 132.1; 148.4; 149.8; 153.7; 154.7; 160.6.
4ꢀ(2ꢀHydroxymethylꢀ4,5ꢀdimethoxyphenyl)ꢀ5,7ꢀdimethoxyꢀ
chromenꢀ2ꢀone (9b) was obtained from compound 6b. The
eluent for column chromatography was AcOEt—light petroꢀ
leum (7 : 3). Yield 67%, colorless powder, m.p. 173—174 °C.
Found (%): C, 64.43; H, 5.43. C20H20O7. Calculated (%):
C, 64.51; H, 5.41. 1H NMR (CDCl3), δ: 3.41, 3.83, 3.86, and
3.95 (all s, 3 H each, OMe); 4.42 (s, 2 H, CH2); 5.97 (s, 1 H,
HC(3)); 6.22 and 6.52 (both d, 1 H each, HC(6), HC(8),
J = 2.4 Hz); 6.60 and 7.05 (both s, 1 H each, HC(3´), HC(6´)).
13C NMR (CDCl3), δ: 55.8; 55.97; 56.0 (intense peak); 62.8;
93.9; 96.2; 104.3; 110.5; 110.7; 113.0; 129.6; 130.8; 147.8; 148.6;
154.0; 156.8; 158.0; 160.6; 163.5.
4ꢀ(4ꢀHydroxyꢀ2ꢀhydroxymethylꢀ5ꢀmethoxyphenyl)ꢀ5,7ꢀdiꢀ
methoxychromenꢀ2ꢀone (10b) was obtained from compound 7b.
The eluent for column chromatography was AcOEt—light peꢀ
troleum (7 : 3). Yield 86%, colorless polycrystalline solid, m.p.
116—117 °C. Found (%): C, 63.54; H, 5.06. C19H18O7. Calcuꢀ
lated (%): C, 63.68; H, 5.06. 1H NMR (CDCl3), δ: 3.43 (s, 3 H,
OMe); 3.86 (s, 6 H, OMe); 4.38 (s, 2 H, ArCH2); 5.98 (s, 1 H,
HC(3)); 6.22 and 6.52 (both d, 1 H each, HC(6), HC(8),
J = 2.2 Hz); 6.59 and 7.07 (both s, 1 H each, HC(3´), HC(6´)).
13C NMR (CDCl3), δ: 55.8; 56.0 (intense peak); 62.7; 93.8;
96.1; 104.3; 109.9; 113.0; 113.9; 130.4; 130.5; 145.3; 145.4; 154.1;
156.8; 158.0; 160.7; 163.4.
4ꢀ(4ꢀHydroxyꢀ2ꢀhydroxymethylꢀ5ꢀmethoxyphenyl)ꢀ5,6,7ꢀ
trimethoxychromenꢀ2ꢀone (10c) was obtained from compound
7c. The eluent for column chromatography was AcOEt—light
petroleum (7 : 3). Yield 82%, colorless polycrystalline solid, m.p.
150—152 °C. Found (%): C, 61.69; H, 5.17. C20H20O8. Calcuꢀ
1
lated (%): C, 61.85; H, 5.19. H NMR (CDCl3), δ: 3.27, 3.77,
3.88 and 3.93 (all s, 3 H each, OMe); 4.33 and 4.40 (both d,
1 H each, CHAHB, CHAHB, J = 8.8 Hz); 5.72 (s, 1 H, ArOH);
6.03 (s, 1 H, HC(3)); 6.75, 7.07 and 7.25 (all s, 1 H each, HC(3´),
HC(6´), HC(8)). 13C NMR (CDCl3), δ: 56.2; 56.4; 61.2; 61.6;
63.1; 97.0; 108.1; 111.3; 113.7; 115.0; 130.0; 131.0; 139.9; 144.6;
146.6; 150.3; 151.4; 153.6; 157.0; 160.5.
4ꢀ(5ꢀHydroxyꢀ2ꢀhydroxymethylꢀ4ꢀmethoxyphenyl)chromenꢀ
2ꢀone (11a) was obtained from compound 8a. The eluent for
column chromatography was AcOEt—light petroleum (1 : 1).
Yield 62%, beige crystals, m.p. 143—144 °C. Found (%):
C, 68.32; H, 4.72. C17H14O5. Calculated (%): C, 68.41; H, 4.73.
1H NMR (CDCl3), δ: 4.00 (s, 3 H, OMe); 4.45 (s, 2 H, ArCH2);
5.73 (s, 1 H, ArOH), 6.34 and 6.81 (both s, 1 H each, HC(3),
HC(3´)); 7.18 (m, 3 H, HC(6´), HC(6), HC(8)); 7.39 (d, 1 H,
HC(5), J = 8.2 Hz); 7.53 (m, 1 H, HC(7)). 13C NMR (CDCl3),
δ: 56.1; 62.3; 110.9; 114.8; 116.2; 117.1; 119.8; 124.3; 126.3;
127.0; 130.3; 132.0; 145.1; 147.4; 153.7; 154.4; 160.6.
4ꢀ(5ꢀHydroxyꢀ2ꢀhydroxymethylꢀ4ꢀmethoxyphenyl)ꢀ5,7ꢀdiꢀ
methoxychromenꢀ2ꢀone (11b) was obtained from compound 8b.
The eluent for column chromatography was AcOEt—light peꢀ
troleum (7 : 3). Yield 88%, colorless polycrystalline solid, m.p.
166 °C. Found (%): C, 63.61; H, 5.07. C19H18O7. Calculatꢀ
4ꢀ(2ꢀHydroxymethylꢀ4,5ꢀdimethoxyphenyl)ꢀ5,6,7ꢀtrimethꢀ
oxychromenꢀ2ꢀone (9c) was obtained from compound 6c. The
eluent for column chromatography was AcOEt—light petroleum
(7 : 3). Yield 62%, transparent crystals, m.p. 177—178 °C.
Found (%): C, 62.79; H, 5.53. C21H22O8. Calculated (%):
1
ed (%): C, 63.68; H, 5.06. H NMR (CDCl3), δ: 3.49, 3.91 and
3.93 (all s, 3 H each, OMe); 4.37 and 4.43 (both d, 1 H each,
CHAHB, CHAHB, J = 7.8 Hz); 5.86 (s, 1 H, HC(3)); 6.38 and
6.57 (both d, 1 H each, HC(6), HC(8), J = 2.4 Hz); 6.65 and
7.16 (both s, 1 H each, HC(3´), HC(6´)). 13C NMR (CDCl3), δ:
56.2; 56.3; 56.4; 62.3; 94.4; 96.3; 111.3; 113.3; 114.9; 131.0;
131.9; 141.3; 143.3; 147.8; 155.1; 157.2; 157.7; 159.5; 164.4.
4ꢀ(5ꢀHydroxyꢀ2ꢀhydroxymethylꢀ4ꢀmethoxyphenyl)ꢀ5,6,7ꢀ
trimethoxychromenꢀ2ꢀone (11c) was obtained from compound
8c. The eluent for column chromatography was AcOEt—light
petroleum (7 : 3). Yield 53%, colorless polycrystalline solid, m.p.
128—129 °C. Found (%): C, 61.99; H, 5.19. C20H20O8. Calcuꢀ
1
C, 62.68; H, 5.51. H NMR (CDCl3), δ: 3.26, 3.77, 3.87, 3.93,
and 3.96 (all s, 3 H each, OMe); 4.38 and 4.43 (both d, 1 H each,
CHAHB, CHAHB, J = 8.4 Hz); 6.05, 6.68, 6.73, and 7.09 (all s,
1 H each, HC(3), HC(8), HC(3´), HC(6´)). 13C NMR (CDCl3),
δ: 56.0; 56.1; 56.3; 61.1; 61.4; 62.9; 96.9; 108.0; 110.7; 111.7;
114.9; 130.1; 130.5; 139.8; 147.8; 149.0; 150.3; 151.3; 153.7;
157.0; 160.3.
4ꢀ(4ꢀHydroxyꢀ2ꢀhydroxymethylꢀ5ꢀmethoxyphenyl)chromenꢀ
2ꢀone (10a) was obtained from compound 7a. The eluent for
column chromatography was AcOEt—light petroleum (1 : 1).
Yield 60%, colorless polycrystalline solid, m.p. 180—181 °C.
Found (%): C, 68.51; H, 4.74. C17H14O5. Calculated (%):
1
lated (%): C, 61.85; H, 5.19. H NMR (CDCl3), δ: 3.28, 3.75,
3.94, and 3.95 (all s, 3 H each, OMe); 4.37 (s, 2 H, ArCH2);

4ꢀ(2ꢀHydroxymethylaryl)coumarins
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
631
6.05, 6.75, 6.97, and 7.08 (all s, 1 H each, HC(3), HC(8), HC(3´),
HC(6´)). 13C NMR (CDCl3), δ: 56.0; 56.3; 60.9; 61.1; 65.0;
96.2; 107.8; 111.5; 114.0; 115.5; 129.8; 130.6; 139.4; 146.0; 149.7;
151.0; 151.4; 153.6; 156.9; 160.5.
5. C. Rappl, P. Barbier, V. BourgarelꢀRey, C. Gregoire, R. Gilli,
M. Carre, S. Combes, J.ꢀP. Finet, V. Peyrot, Biochemistry,
2006, 45, 9210.
6. (a) M. Cushman, D. Nagaratham, D. Gopal, A. K. Chakꢀ
raborti, C. M. Lin, E. J. Hamel, J. Med. Chem., 1991, 34,
2579; (b) K. Ohsumi, T. Hatanaka, K. Fujita, R. Nakagawa,
Y. Fukuda, Y. Nihei, Y. Suga, Y. Morinaga, Y. Akiyama,
T. Tsuji, Bioorg. Med. Chem. Lett., 1998, 8, 3153.
7. M. I. Naumov, S. A. Sutirin, A. S. Shavirin, O. G. Ganina,
V. BourgarelꢀRey, I. P. Beletskaya, J.ꢀP. Finet, A. Yu. Feꢀ
dorov, J. Org. Chem., 2007, 72, 3293.
8. (a) M. F. Oldfield, L. Chen, N. P. Botting, Tetrahedron,
2004, 60, 1887; (b) R. A. Dixon, D. Ferreira, Phytochemisꢀ
try, 2002, 16, 205; (c) H. Adlercreutz, Lancet Oncol., 2002,
3, 364; (d) C. Morrisey, R. W. G. Watson, Curr. Drug Tarꢀ
gets, 2003, 4, 231.
4ꢀ(2ꢀChloromethylꢀ4ꢀhydroxyꢀ5ꢀmethoxyphenyl)chromenꢀ2ꢀ
one (12) was obtained along with product 10a. The eluent for
column chromatography was AcOEt—light petroleum (1 : 1).
Yield 25%, colorless polycrystalline solid, m.p. 192—193 °C.
Found (%): C, 64.26; H, 4.15. C17H13ClO4. Calculated (%): C,
1
64.46; H, 4.14. H NMR (CDCl3), δ: 3.89 (s, 3 H, OMe); 4.28
and 4.38 (both d, 1 H each, CHAHB, CHAHB, J = 9.0 Hz); 5.91
(s, 1 H, ArOH); 6.43 and 6.69 (both s, 1 H each, HC(3), HC(3´));
7.20 (m, 3 H, HC(6´), HC(6), HC(8)); 7.40 (d, 1 H, HC(5),
J = 7.8 Hz); 7.55 (m, 1 H, HC(7)). 13C NMR (CDCl3), δ: 43.4;
56.2; 111.0; 116.6; 116.8; 117.2; 119.8; 124.4; 126.3; 127.0; 128.4;
132.2; 146.6; 146.8; 153.8; 153.9; 160.4.
9. (a) N. Miyaura, A. Suzuki, Chem. Rev., 1995, 95, 2457;
(b) A. Suzuki, J. Organomet. Chem., 1999, 576, 147;
(c) P. LlordꢀWilliams, E. Giralt, Chem. Soc. Rev., 2001, 30,
145; (d) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz,
M. Lamaire, Chem. Rev., 2002, 102, 1359.
10. (a) D. H. R. Barton, D. M. X. Donnelly, J.ꢀP. Finet, P. G.
Guiry, J. Chem. Soc., Perkin Trans. 1, 1992, 1365; (b) G. M.
Boland, D. M. X. Donnelly, J.ꢀP. Finet, M. Rea, J. Chem.
Soc., Perkin Trans. 1, 1996, 2591; (c) D. M. X. Donnelly,
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29, 2719.
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos 09ꢀ03ꢀ00647ꢀa
and 09ꢀ03ꢀ97038ꢀpꢀPovolzh´eꢀa), the Council on Grants
at the President of the Russian Federation (State Support
Program for Leading Scientific Schools of the Rusꢀ
sian Federation and Young D.Sc. Scientists, Grant
MDꢀ5606.2010.3), and the German Academic Exꢀ
change Service (der deutsche akademische Austauschdiꢀ
enst (DAAD), A0879551).
11. O. G. Ganina, E. Daras, V. BourgarelꢀRey, V. Peyrot, A. N.
Andresyuk, J.ꢀP. Finet, A. Yu. Fedorov, I. P. Beletskaya,
S. Combes, Bioorg. Med. Chem., 2008, 16, 8806.
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Received May 5, 2009;
in revised form December 17, 2009