Reductive cyclization of a functionalized 1,1′-bianthraquinone

Article abstract of DOI:10.1055/s-2005-871943

Reductive cyclization of 2,2′-dimethoxymethyl-[1,1′- bianthracene]-9,9′, 10,10′-tetrone with Cu powder in concentrated sulfuric acid yields helianthrone with partially reduced side chain. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871943

LETTER
1905
Reductive Cyclization of a Functionalized 1,1¢-Bianthraquinone
R
eductiv
s
e
Cycliza
a
tion of
a
Fu
b
nctionalized
e
1,1
¢
-Bianth
l
raquinone Maria Althön, Dietrich Spitzner*
Institut für Chemie, Abt. Bioorganische Chemie, Universität Hohenheim, Garbenstraße 30, 70593 Stuttgart, Germany
Fax +49(711)4593703; E-mail: spitzner@uni-hohenheim.de
Received 23 May 2005
In memoriam Professor Dr. Dr. E.h. Hans Brockmann (1903–1988).
This method cannot easily be applied to the synthesis of
1b or 2b from side chain oxidized emodins due to the in-
stability of 1b and 2b, respectively, in alkaline solutions.
On the other hand, 2b forms cyclopseudohypericin (2c)
upon photolysis in concentrated sulfuric acid.9 In order to
have access to compounds of type 1b we investigated
the reductive cyclization of 1,1¢-bianthraquinones and
applied the method of R. Scholl et al.11–13 to compound 7.
Abstract: Reductive cyclization of 2,2¢-dimethoxymethyl-[1,1¢-bi-
anthracene]-9,9¢,10,10¢-tetrone with Cu powder in concentrated sul-
furic acid yields helianthrone with partially reduced side chain.
Key words: ring closure, reduction, cyclization, fused-ring systems
Quinoid natural products possessing a helianthrone
(dibenzo[a,o]perylene-7,16-dione) or a meso-naphtho-
dianthrone (phenanthro[1,10,9,8-opqra]perylene-7,14-
dione) skeleton are interesting photodynamic compounds
and synthetic photosensitizers. Irradiation of heli-
anthrones with visible light leads to the formation of
semiquinone radicals and reactive oxygen species.1–4 He-
lianthrones are easily photooxidized to form the corre-
sponding meso-naphthodianthrones. Typical natural
compounds are e.g. the protohypericins (1). Both 1 and
hypericins 2a,b (Figure 1) have been isolated from Hy-
pericum spp.;5–9 2a has been prepared biomimetically via
1a from 3b, emodin-9-anthrone or emodin by phenol
oxidation in basic medium followed by photooxidation.10
O
O
Cu, naphthalene,
CH2OMe
O
reflux
O
R
56%
MeOH2C
O
Cl
4 R = Me
5 R = CH2Br
6 R = OMe
a: NBS, CCl4, 75%
b: NaOMe–benzene, r.t., 65%
O
7
Scheme 1
The bianthraquinone 7 was prepared by a straight forward
sequence: bromination of 4 in tetrachloromethane gave
the bromomethyl compound 5 in good yield (75%).14 The
bromine atom was replaced by a methoxy group with so-
dium methoxide in MeOH at room temperature to yield 6
(65%).15 Ullmann reaction16 (activated Cu powder in
naphthalene at 235 °C, 3 h) gave the functionalized 1,1¢-
bianthraquinone 7 (56%, Scheme 1). Surprisingly, the re-
ductive cyclization of 7 using activated Cu powder in con-
centrated sulfuric acid at –5 °C was very fast but we
obtained not the expected helianthrone 8 but a mixture of
compound 11 and the oxepine 10 instead (Scheme 2).17
Longer exposure of 7 to Cu powder in concentrated sulfu-
ric acid resulted in the formation of 9. Helianthrone 11
OH
O
OH
1a protohypericin, R, R1 = Me
b
protopseudohypericin, R1 = CH2OH,
R = Me
HO
HO
R
R1
OH
O
OH
OH
O
OH
HO
HO
Me
Me
X2
X2
OH
O
OH
1
shows in the H NMR spectrum an AB spin system
HO
HO
R
R1
(JAB = 12 Hz) for the diastereotopic hydrogens of the
CH2O group. The 1H NMR spectrum of 1b shows a simi-
lar pattern.6
OH
O
OH
3a skyrin, X2 = O
penicilliopsin, X = H
b
An AB spin system (JAB = 12 Hz) is observed for the
methylene groups of the 2,7-dihydrooxepin moiety of 10,
and it indicates the non equivalence of the hydrogens of
the CH2 groups next to the chiral helianthrone chromo-
phore.
OH
O
OH
2a hypericin, R, R1 = Me
b
c
pseudohypericin,
1 = CH2OH, R = Me
R
cyclopseudohypericin,
R–R1 = CH=CH
The cyclization of 7 with Cu powder in glacial acetic
acid–HCl (concd) at room temperature13 to form heli-
anthrone 8 failed. Compounds 1a and 2a cannot be made
from skyrin (3a) since it is reductively cleaved to form
emodin [both in sulfuric acid (concd) and glacial acetic
acid–HCl (concd)].
Figure 1
SYNLETT 2005, No. 12, pp 1905–1906
Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871943; Art ID: G13205ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.0
8
.2
0
0
5

1906
I. M. Althön, D. Spitzner
LETTER
O
dried (Na2SO4), and filtered over Al2O3 (neutral). Elution
with toluene gave a yellow filtrate, which was concentrated
to yield 10.00 g (65%) of yellow crystals, mp 180 °C.
1H NMR (300 MHz, CDCl3): d = 8.30–7.70 (m, 5 H), 4.75
(s, 2 H, CH2), 3.61 (s, 3 H, OMe). Anal. Calcd for
C16H11O3Cl (286.7): Cl, 12.4. Found: Cl, 12.62.
Cu (activ.) – concd
H2SO4, –5 °C, 5 min
R
R
7
(16) (a) Fanta, P. E. Synthesis 1974, 9. (b) Preparation of
Compound 7.
O
Activation of Cu-powder: commercially available Cu
powder (Merck, Darmstadt, Germany) was treated in glacial
acetic acid at r.t. for 10 min. The mixture was filtered and the
filter cake washed with H2O until neutral. The treatment was
repeated and the activated Cu was finally washed with
acetone and dried in vacuo at r.t. and stored under an
atmosphere of argon. Activated Cu powder was introduced
into a melt of 6 (10.00 g, 34.9 mmol) in naphthalene (14 g)
with stirring. The reaction mixture was kept at 235 °C for 3
h, cooled to r.t. and the crashed cake was extracted with
CHCl3. The filtered solution was concentrated and the
residue dissolved in toluene (20 mL). This solution was
adsorbed on silica gel. Elution with toluene gave after the
fast removing of naphthalene a yellow filtrate which was
concentrated to give 6.00 g of crude 7. The crude product
was crystallized from hot EtOH to yield 5.00 g (56%),
yellow plates, mp 226–227 °C (EtOH). 1H NMR (300 MHz,
CDCl3): d = 8.572–8.545 (d, J = 8 Hz, 1 H), 8.344–8.316
(dd, J = 0.9, 7.6 Hz, 1 H), 8.102–8.076 (d, J = 8 Hz, 1 H),
7.999–7.970 (dd, J = 1.0, 7.6 Hz, 1 H), 7.796–7.741 (ddd,
J = 1.0, 7.6, 7.3 Hz, 1 H), 7.714–7.659 (ddd, J = 1.0, 7.5, 7.6
Hz, 1 H), 3.40 (s, 2 H, CH2), 3.17 (s, 3 H, CH3). 13C NMR
(75.48 MHz, CDCl3): d = 183.85 (s), 183.50 (s), 142.81 (s),
139.94 (s), 134.32 (s), 134.30 (d), 134.08 (d), 133.33 (s),
133.29 (d), 130.75 (s), 127.53 (d), 127.47 (d), 127.12 (d),
72.03 (t), 58.89 (q). MS: m/z (%) = 502 (8)[M]+, 470 (100),
409 (30), 383 (20). IR (KBr): 1668 cm–1 (C=O). UV (EtOH):
lmax (log e) = 254 nm (4.53), 336 (3.62). Anal. Calcd for
C32H22O6 (502.5): C, 76.48; H, 4.41. Found: C, 76.62; H,
4.39.
8 R = CH2OMe
9 R = Me
O
O
CH2OMe
CH3
O
O
O
11
10
Scheme 2
Acknowledgment
We thank the BASF AG, Ludwigshafen, Germany, for chemicals.
References
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(17) Preparation of Compounds 10 and 11.
To the dark brown solution of 7 (1.01 g, 20 mmol) in concd
H2SO4 (60 mL) at –5 °C was added Cu powder (5 g) with
stirring in the dark. Soon, the solution became green. The
reaction mixture was poured on ice (200 g) after 5 min. The
precipitate was filtered off, washed with H2O until neutral
and dissolved in CHCl3. The organic solution was dried
(Na2SO4) and concentrated, and the brown residue (1.00 g)
was dissolved in benzene (50 mL). The crude product was
chromatographed on silica gel in the dark to avoid
photocyclization. Elution with benzene gave 0.150 g (18%)
10 (eluted first) and 0.100 g (11%) 11.
(5) Brockmann, H. Fortschr. Chem. Org. Naturst. 1957, 14,
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Tetrahedron Lett. 1974, 1991.
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Compound 10: red needles, mp >240 °C. 1H NMR (300
MHz, CDCl3): d = 8.84 (d, J = 7.6 Hz, 2 H), 8.47 (d, J = 8
Hz, 2 H), 7.96 (dd, J = 8.2, 7.8 Hz, 4 H), 7.57 (dd, J = 8.2,
6.9 Hz, 2 H), 7.39 (dd, J = 7.5, 7.0 Hz, 2 H), 5.06 and 4.52
(AB, JAB = 12.0 Hz, 4 H, -CH2-O-). 13C NMR (75.48 MHz,
CDCl3): d = 184.1 (s), 141.8 (s), 137.1 (s), 133.1 (d), 132.4
(s), 131.9 (d), 131.7 (s), 131.0 (s), 130.0 (d), 129.7 (d), 129.1
(d), 129.0 (s), 128.0 (d), 127.5 (s), 70.61 (t). MS: m/z (%) =
424 (51)[M]+, 395 (20), 236 (35), 28 (100). UV (EtOH): lmax
(log e) = 457 nm (3.75), 353 (3.46), 316 (3.39), 236 (4.19).
Anal. Calcd for C31H20O3 (424.4): C, 84.89; H, 3.80. Found:
C, 84.48; H, 3.77.
(14) Scharf, H. D.; Weitz, R. Tetrahedron 1979, 35, 2263.
(15) Preparation of Compound 6.
Compound 11: red needles, mp >240 °C. 1H NMR (300
MHz, CDCl3): d = 8.85–7.33 (m, 12 H), 5.05 and 4.50 (AB,
JAB = 12 Hz, 2 H, -CH2-O-), 3.13 (s, 3 H, OMe), 2.63 (s, 3 H,
Me). MS: m/z (%) = 440 (60)[M]+, 407 (60), 28 (100). Anal.
Calcd for C30H16O3 (440.5): C, 84.53; H, 4.58. Found: C,
84.70; H, 4.43.
To a solution of 5 (18.00 g, 53.6 mmol) in toluene (700 mL)
was added with stirring a freshly prepared solution of
NaOMe [Na (4.00 g, 173 mmol) and MeOH (200 mL)] at r.t.
The red reaction mixture was diluted with H2O after 3 h, the
organic phase was separated, washed with H2O until neutral,
Synlett 2005, No. 12, 1905–1906 © Thieme Stuttgart · New York