Syntheses of anthracenones. 3. Revised preparative route to 10-Benzoyl-1,8-dihydroxy-9(10H)-anthracenones

Article abstract of DOI:10.1021/jo952037l

The acylation of anthralin (1,8-dihydroxy-9(10H)-anthracenone) with acetylsalicylic acid chloride in toluene and collidine was found to give the O-acylated product, rather than 10-(acetylsalicyl)-anthralin. A procedure is described for benzoylation of anthralin in the 10-position which involves reaction of 1,8-diacetoxy-9(10H)-anthracenone with benzoyl chloride and sodium hydride in THF followed by hydrolysis of an intermediate enol ester. Furthermore, when benzoyl chloride and DMF were used for the acylation of anthralin, a Vilsmeier-type reaction was observed leading to a novel enamine derivative of anthralin which was hydrolyzed or benzoylated to an enol or enol ester, respectively.

Full text of DOI:10.1021/jo952037l

J . Org. Chem. 1996, 61, 2861-2864
2861
Syn th eses of An th r a cen on es. 3. Revised P r ep a r a tive Rou te to
10-Ben zoyl-1,8-d ih yd r oxy-9(10H)-a n th r a cen on es
Helge Prinz, Wolfgang Wiegrebe, and Klaus Mu¨ller*
Institut fu¨r Pharmazie, Pharmazeutische Chemie I, Universita¨t Regensburg,
D-93040 Regensburg, Germany
Received November 16, 1995X
The acylation of anthralin (1,8-dihydroxy-9(10H)-anthracenone) with acetylsalicylic acid chloride
in toluene and collidine was found to give the O-acylated product, rather than 10-(acetylsalicyl)-
anthralin. A procedure is described for benzoylation of anthralin in the 10-position which involves
reaction of 1,8-diacetoxy-9(10H)-anthracenone with benzoyl chloride and sodium hydride in THF
followed by hydrolysis of an intermediate enol ester. Furthermore, when benzoyl chloride and
DMF were used for the acylation of anthralin, a Vilsmeier-type reaction was observed leading to
a novel enamine derivative of anthralin which was hydrolyzed or benzoylated to an enol or enol
ester, respectively.
In tr od u ction
Structure-activity relationships revealed that the
mere presence of an acyl substituent at C-10 of anthralin
does not necessarily lead to enhanced activity, and it was
demonstrated that a terminal phenyl ring is required.8
However, a major obstacle encountered in this study has
been the lack of a convenient and effective method for
the preparation of 10-benzoyl derivatives of anthralin,
the lowest homologs in this series. These compounds are
of particular interest, since they lack methylene units
linking the terminal phenyl and the carbonyl group at
C-10. This suggests a strong impact on anthracenone
radical formation and redox properties, depending on the
nature of the substituents on the terminal phenyl ring.
Although the acylation with ω-phenyl terminated acyl
chlorides proceeded smoothly, benzoyl chlorides, under
identical reaction conditions, did not result in the antici-
pated 10-benzoyl derivatives, but exclusively gave a
mixture of mono- and diesters of the 1- and 8-hydroxyl
groups. On the basis of these observations and in search
for an appropriate solution for this problem, we have
developed an alternative preparative route to 10-benzoyl
derivatives of anthralin.
In our preceding papers,1,2 we reported on selective
syntheses of isomers and other derivatives of the antip-
soriatic drug anthralin (1, 1,8-dihydroxy-9(10H)-anthra-
cenone). However, its therapeutic use is accompanied by
severe inflammation and staining of the skin. These side
effects may be interpreted in terms of the efficacy of the
anthracenones to generate oxygen radicals.3,4 It is now
well established that 1,8-dihydroxy-9(10H)-anthracenones
easily undergo one-electron oxidation to produce radical
intermediates, including anthracenon-9-yl radicals and
secondary radicals.5 Coincident with this process is the
generation of reactive oxygen species. The methylene
moiety at C-10 has been recognized as a key site of the
formation of superoxide radical, which in turn can
dismutate to produce hydrogen peroxide, and in the
presence of iron, the highly reactive hydroxyl radical.6
Data of ESR studies and molecular calculations are
consistent with an anthracenone radical structure con-
taining a carbon-centered radical at the bridging 10-
carbon.7 It was anticipated that appropriate chemical
modification of anthralin might provide agents with
diminished oxygen-radical formation.8,9 In particular,
substitution with an electron-withdrawing acyl group at
the 10-position impairs the reduction power of anthra-
cenones.10 We have applied such rationale to the syn-
thesis of 10-ω-phenylacyl derivatives with modulated
redox properties.8 The compounds were prepared by
reaction of the appropriate acyl chlorides with anthralin
in toluene and pyridine. Under these conditions acyla-
tion takes place at C-10 via the carbanion.
Resu lts a n d Discu ssion
The only study aimed at the synthesis of anthralin
derivatives with free phenolic groups and a 10-benzoyl
substituent which has so far appeared in the literature
is by Berset al.11 In this approach, the acid chloride of
acetylsalicylic acid was reacted with 1 in toluene and
collidine, and the structure of the obtained product was
assigned to 10-(acetylsalicyl)anthralin (2, Scheme 1). On
1
the basis of reported H NMR and IR data the structure
* To whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, April 1, 1996.
(1) Prinz, H.; Wiegrebe, W.; Mu¨ller, K. J . Org. Chem. 1996, 61, 2853.
(2) Prinz, H.; Burgemeister, T.; Wiegrebe, W.; Mu¨ller, K. J . Org.
Chem. 1996, 61, 2857.
(3) Mu¨ller, K.; Gu¨rster, D. Biochem. Pharmacol. 1993, 46, 1695.
(4) Mu¨ller, K. Gen. Pharmacol., in press.
(5) Hayden, P. J .; Free, K. E.; Chignell, C. F. Mol. Pharmacol. 1994,
46, 186.
(6) Mu¨ller, K.; Kappus, H. Biochem. Pharmacol. 1988, 37, 4277.
(7) Motten, A. G.; Sik, R. H.; Chignell, C. F.; Hayden, P. J . Chem.
Res. Toxicol. 1994, 7, 877.
assignment of 2 is questionable, and the compound may
be an oxygen acylated rather than a C-10 acylated
derivative. This prompted us to reinvestigate the syn-
thetic utility of this reaction. Attempts to prepare 2
using this method failed in our hands. Only the O-
acylated 1-[(2-acetoxybenzoyl)oxy]-8-hydroxy-9(10H)-an-
thracenone (3) was isolated as a reaction product, as
1
evidenced by the H NMR spectrum. In fact, compound
3 prepared according to the method of Berset et al.11 did
not reveal the characteristic downfield shift for the C-10
proton of 10-acylated anthralin derivatives compared to
(8) Mu¨ller, K.; Gu¨rster, D.; Piwek, S.; Wiegrebe, W. J . Med. Chem.
1993, 36, 4099.
(9) Mu¨ller, K.; Leukel, P.; Ziereis, K.; Gawlik, I. J . Med. Chem. 1994,
37, 1660.
(10) Pecar, S.; Schara, M.; Mu¨ller, K.; Wiegrebe, W. Free Radical
Biol. Med. 1995, 18, 459.
(11) Berset, J .-D.; Krebs, A. Pharm. Acta Helv. 1990, 65, 14.
0022-3263/96/1961-2861$12.00/0 © 1996 American Chemical Society

2862 J . Org. Chem., Vol. 61, No. 8, 1996
Prinz et al.
Sch em e 1a
drolysis and obtained 10-formylanthralin as the enol
tautomer 9. The absence of an aldehyde absorption in
the IR spectrum confirmed that no tautomerization to
the 10-formyl derivative took place. In further support
of this, the 1H NMR spectrum, recorded in DMSO-d6,
displayed no signal for an aldehydic proton, but a
resonance at δ 8.47 corresponding to the proton at the
enol carbon. As in compounds 7 and 8, this signal is
clearly distinguished from the aromatic protons.
A
possible mechanism for the formation of 9 is given in
Scheme 2. In nonpolar aprotic solvents anthralin exists
as the anthracenone tautomer exclusively,12-14 whereas
the 1,8,9-trihydroxyanthracene could only be identified
in hexamethylphosphoric triamide.12 When bases are
added or when anthralin is dissolved in polar aprotic
solvents it is partially converted to its anion 1a ,14-16
which is the predominant form in basic solutions and in
DMF.14,17 On the basis of computational studies, the
ionization site for anthralin was predicted to be at the
10-position.18 The formation of 7 is without precedence
but can be rationalized in a straightforward manner as
a process involving electrophilic substitution at the 10-
position of the quite electron-rich, nucleophilic polyhy-
droxyanthracene anion 1a of anthralin thus formed in
DMF. In such a Vilsmeier-type reaction, the disubsti-
tuted formamide will be activated by benzoyl chloride,
in place of the more common POCl3, and the attacking
species is 10, which has already been described as the
reactive intermediate in the preparation of formami-
dinium salts using benzoyl chloride and DMF in the
presence of a carboxamide.19 The intermediate 11 may
eliminate benzoic acid to give the enamine 7 or hydrolyze
to 9. Modified Vilsmeier reactions using benzoyl chloride
in place of POCl3 have also been described for the
formylation of other substrates.20,21
a
Reagents: (a) acetylsalicylic acid chloride, collidine or pyridine,
toluene; (b) benzoyl chloride, pyridine or hexamethylphosphoric
triamide; (c) benzoyl chloride, NaH, THF.
Sch em e 2a
In further attempts to obtain the desired 10-benzoyl-
anthralin, we envisaged protection of the free phenolic
groups of 1 in order to prevent O-acylation. To this end,
a versatile protecting group is required which is intro-
ducable with respect to the C-10 reactivity of 1 and
selectively removable under conditions that would not
affect the C-10 benzoyl substituent. At the beginning of
our studies a promising preparative procedure involved
reaction of the 1,8,9-tris(trimethylsilyl) ether22 of 1 with
benzoyl chloride. Unfortunately, Friedel-Crafts condi-
tions (aluminum chloride, carbon disulfide, argon) which
convert the trimethylsilyl ether of 9-anthracenol and
benzoyl chloride to 10-benzoyl-9(10H)-anthracenone,23
gave only 1 when 1,8,9-tris[(trimethylsilyl)oxy]anthra-
cene was used.
a
Reagents: (a) benzoyl chloride, DMF; (b) H2O, benzoyl chlo-
ride; (c) HCl, H2O.
the signal of C-10 unsubstituted anthralin. Integration
of the peak area confirmed the presence of two protons
at C-10. Hence, an alternative preparative route was
required.
Attempted modifications of the standard method for
the preparation of 10-acyl anthralin derivatives were
unsuccessful; in spite of varying the base, the base-to-
anthrone-ratio, the solvent, the order of additions, and
the time and temperature, only the O-benzoylated com-
pounds 4 and 5 were obtained from the reaction of 1 and
benzoyl chloride. In addition, when sodium hydride was
used as a base in THF, benzoylation of 1 gave a tetra-
benzoylated compound 6 (Scheme 1).
Furthermore, use of the recently described 1,8-dimeth-
oxy-9-hydroxyanthracene2 (12) was studied. Friedel-
Crafts reaction with benzoyl chloride gave the expected
(12) Geiger, W. Chem. Ber. 1974, 107, 2976-2984.
(13) Avdovich, H. W.; Neville, G. A. Can. J . Spectrosc. 1980, 25, 110.
(14) Mu¨ller, K.; Mayer, K. K.; Wiegrebe, W. Arch. Pharm. (Wein-
heim) 1986, 319, 1009.
(15) Wiegrebe, W.; Retzow, A.; Plumier, E. Br. J . Dermatol. 1981,
105 (Suppl. 20), 12.
(16) Koerner, M.; Rickborn, B. J . Org. Chem. 1990, 55, 2662.
(17) Sa e Melo, T.; Dubertret, L.; Prognon, P.; Gond, A.; Mahuzier,
G.; Santus, R. J . Invest. Dermatol. 1983, 80, 1.
(18) Holder, A. J .; Upadrashta, S. M. J . Pharm. Sci. 1992, 81, 1074.
(19) Finkbeiner, H. J . Org. Chem. 1965, 30, 2861.
(20) Chong, R.; Clezy, P. S.; Liepa, A. J .; Nichol, A. W. Aust. J . Chem.
1969, 22, 229.
(21) Horning, D. E.; Muchowski, J . M. Can. J . Chem. 1970, 48, 193.
(22) Prognon, P.; Gond, A.; Dubertret, L.; Mahuzier, G. Ann. Pharm.
Fr. 1982, 40, 329.
Interestingly, when DMF was used as solvent, the
O-benzoyl derivatives were not obtained, but rather a
novel enamine derivative 7 of anthralin was isolated,
along with the enol ester 8 (Scheme 2), which may be
formed from the enamine 7 as a consequence of aqueous
reaction workup. We subjected the enamine 7 to hy-
(23) Camaioni, D. M.; Alnajjar, M. S. J . Org. Chem. 1985, 50, 4456.

Syntheses of Anthracenones. 3
Sch em e 3a
J . Org. Chem., Vol. 61, No. 8, 1996 2863
set et al.11 envisaged the synthesis of this derivative as
their initial goal, since they expected a greater impact
on the therapeutic need by combination of anthralin and
the keratolytic activity of salicylic acid within one
molecule. However, hydrolysis of their putative 10-
(acetylsalicyl)anthralin failed to give 18,11 since the
correct structure of their compound is the phenol ester
3, which can only be hydrolyzed to 1.
In conclusion, 10-benzoyl- and 10-salicylanthralin have
both been synthesized for the first time from anthralin
using a three-step route applicable to the synthesis of
novel anthracenones substituted on the benzoyl moiety,
which forms the basis of ongoing studies. Furthermore,
our results of the attempted benzoylation of anthralin
in DMF seem to be consistent with a Vilsmeier-type
reaction having occurred to produce an enamine which
was then hydrolyzed or benzoylated to an enol or enol
ester, respectively.
a
Reagents: (a) benzoyl chloride, AlCl3, 1,2-dichloroethane, 0-5
°C; (b) BBr3, CH2Cl2, -78 °C.
Sch em e 4a
Exp er im en ta l Section
Gen er a l. For analytical instruments and methods, see ref
8. Melting points were determined on a Bu¨chi 510 melting
point apparatus and are uncorrected. 1H NMR spectra were
recorded with a Varian EM 390 (90 MHz) or a Bruker WM
250 (250 MHz), using tetramethylsilane as an internal stan-
dard. Fourier-transform IR spectra (KBr) were recorded on a
Nicolet 510M FTIR spectrometer. Mass spectra were obtained
on a Varian MAT 112S, EI-MS (70 eV); relative intensities
are given in parentheses. Thin layer chromatography (TLC)
was conducted on Merck Kieselgel 60 F254 precoated silica gel
plates. Column chromatography was performed on Merck
silica gel (70-230 mesh) with CH2Cl2 as eluant, unless
otherwise stated. Elemental analyses were determined by the
Microanalytical Laboratories at the University of Regensburg.
1-(2-Ac e t o x y b e n z o y l)-8-h y d r o x y -9(10H )-a n t h r a -
cen on e (3). Following the method of Berset,11 1 (2.26 g, 10
mmol) was dissolved in dry toluene (40 mL) and cooled to 0
°C. Collidine (1.82 g, 15 mmol) was added under N2 and then
acetylsalicylic acid chloride (1.99 g, 10 mmol) dropwise within
30 min, and the mixture was brought to room temperature in
the course of 6 h. Then it was filtered by suction and
evaporated. Purification by column chromatography afforded
yellow needles: 28% yield; mp 168 °C; 1H NMR (250 MHz,
CDCl3) δ 12.62 (s, 1 H), 8.38-6.84 (m, 10 H), 4.38 (s, 2 H),
2.31 (s, 3 H). Anal. Calcd for C23H16O6: C, 71.13; H, 4.15.
Found: C, 71.07; H, 4.17. The analytical data are identical
with those of an authentic sample of Berset’s11 compound.
1-(Ben zoyloxy)-8-h ydr oxy-9(10H)-an th r acen on e (4). To
a solution of 1 (0.45 g, 2 mmol) in HMPTA (15 mL) was added
benzoyl chloride (0.84 g, 6 mmol), and the solution was stirred
for 12 h at room temperature. Then the mixture was poured
into water (500 mL) and extracted with ether (2 × 50 mL).
The combined organic phase was washed with water (3 × 50
mL), dried over Na2SO4, and evaporated. Purification by
column chromatography afforded a pale yellow powder: 43%
a
Reagents: (a) benzoyl chloride or acetylsalicylic acid chloride,
NaH, THF, room temperature, N2; (b) 9% NaOH, ethanol, room
temperature, N2.
10-benzoylated 9-hydroxyanthracene 13 (Scheme 3). The
10-hydroxy proton chemical shift at δ 11.32 supports the
presence of this tautomeric form. However, deprotection
of both methyl ethers of 13 with boron tribromide
resulted also in loss of the benzoyl function at C-10,
yielding 1 as the sole product.
Finally, use of the more readily removable acetyl group
was studied. Thus, anthralin diacetate 1424 was treated
with benzoyl chloride and sodium hydride in THF, but
did not afford the expected 10-benzoylated product.
Alternatively, the enol ester 15 was isolated (Scheme 4).
Nonetheless, hydrolysis of 15 yielded the desired 10-
benzoylanthralin (16). Thus, debenzoylation of 15 pro-
duces an intermediate enol which is further deacetylated
(or vice versa) and tautomerizes to 16. Our hydrolytic
conditions use 9% aqueous sodium hydroxide and require
continuous TLC controls to avoid degradation to 1.
Characterization of 16 by 1H NMR spectroscopy revealed
a large 1.8 ppm downfield shift for the C-10 proton
compared to that of 1,13 even larger than the shifts (0.8
ppm) observed for the 10-ω-phenylacyl analogs.8 Thus,
this proton is located in the 10-benzoyl phenyl ring’s
shielding region.
1
yield; mp 173 °C; FTIR 1733, 1631 cm-1; H NMR (90 MHz,
CDCl3) δ 12.72 (s, 1 H), 8.37-6.78 (m, 11 H), 4.38 (s, 2 H); MS
m/ z ) 330 (32, M+). Anal. Calcd for C21H14O4: C, 76.34; H,
4.27. Found: C, 76.23; H, 4.56.
1,8-Bis(ben zoyloxy)-9(10H)-a n th r a cen on e (5) was pre-
pared as described for 4, but pyridine was used instead of
HMPTA. After the reaction was complete, the mixture was
poured into 3.5% HCl (100 mL) and extracted with CH2Cl2 (2
× 50 mL): 64% yield; mp 210 °C (lit.25 mp 214-216 °C).
1,8,9-Tr is(ben zoyloxy)-10-ben zoyla n th r a cen e (6). To a
suspension of 1 (0.50 g, 2.21 mmol) in absolute THF (20 mL)
was added NaH (0.50 g) under N2 and then benzoyl chloride
(1.86 g, 13.26 mmol) dropwise. After the reaction was com-
plete, the mixture was stirred for 1 h. Then the mixture was
Similarly, enol ester 17 was produced in 64% yield from
the reaction of acetylsalicylic acid chloride and 14, which
was readily hydrolyzed to 10-salicylanthralin (18). Ber-
(24) Wiegrebe, W.; Gerber, A.; Kappler, J .; Bayerl, C. Arzneim.-
Forsch. 1979, 29, 1083.
(25) Paal, M.; Pape, W.; Raap, A. Ger. Offen. DE 4,231,636 (Cl.
C07C69/18) 1994; Chem. Abstr. 1994, 121, 82745a.

2864 J . Org. Chem., Vol. 61, No. 8, 1996
Prinz et al.
poured into ice-water (300 g) and 37% HCl (20 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined organic
phase was washed with water (3 × 100 mL), dried over Na2-
SO4, and evaporated. Purification by column chromatography
afforded a pale yellow powder: 58% yield; mp 260 °C; FTIR
N2. The solution was allowed to warm to room temperature,
stirred for 24 h, poured into water (200 mL), and stirred for
an additional 15 min, and the mixture was extracted with CH2-
Cl2 (2 × 30 mL). The combined organic phase was washed
with water (2 × 40 mL), dried over Na2SO4, and evaporated.
Purification by column chromatography afforded 1 as the sole
product.
1
1740, 1661 cm-1; H NMR (90 MHz, CDCl3) δ 8.17-6.42 (m,
26 H); MS m/ z ) 642 (8, M+). Anal. Calcd for C42H26O7: C,
78.50; H, 4.08. Found: C, 78.07; H, 4.34.
1,8-Dia cetoxy-10-[1-(ben zoyloxy)-1-p h en ylm eth ylen e]-
9(10H)-a n th r a cen on e (15). To a suspension of NaH (0.30
g) in absolute THF (25 mL) was added 1426 (0.31 g, 1 mmol)
under N2, and the mixture was stirred at room temperature
for 15 min. Benzoyl chloride (0.84 g, 6 mmol) was added in
one portion, and the mixture was stirred for 1 h. After the
reaction was complete, the mixture was stirred once more for
1 h. It was then poured into water (200 mL) and 37% HCl
(20 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined
organic phase was washed with water (3 × 50 mL), dried over
Na2SO4, and evaporated. Purification by column chromatog-
raphy afforded a pale yellow powder: 53% yield; mp 169 °C;
1,8-Dih yd r oxy-10-[(N,N-d im et h yla m in o)m et h ylen e]-
9(10H)-a n th r a cen on e (7). To a solution of 1 (1.00 g, 4.42
mmol) in dry DMF (20 mL) was added benzoyl chloride (0.62
g, 4.42 mmol) in one portion under N2, and the solution was
stirred until the reaction was complete (TLC control). Then
the mixture was poured into ice-water (500 g) and extracted
with ether (3 × 100 mL). The combined organic phase was
washed with water (4 × 100 mL), dried over Na2SO4, and
evaporated. Purification by column chromatography (ether)
afforded dark-red crystals: 51% yield; mp 131 °C; FTIR 1607
cm-1; 1H NMR (90 MHz, CDCl3) δ 13.98 (s, 2 H), 8.02 (s, 1 H),
7.52-6.52 (m, 6 H), 3.02 (s, 6 H); MS m/ z ) 281 (100, M+).
Anal. Calcd for C17H15O3N: C, 72.58; H, 5.37; N, 4.98.
Found: C, 72.45; H, 5.38; N, 5.00.
FTIR 1771, 1746, 1671 cm-1 1H NMR (90 MHz, CDCl3) δ
;
7.93-7.00 (m, 16 H), 1.72 (s, 6 H); MS m/ z ) 518 (2, M+).
Anal. Calcd for C32H22O7: C, 74.12; H, 4.28. Found: C, 74.28;
H, 4.48.
1,8-Dih yd r oxy-10-[(ben zoyloxy)m eth ylen e]-9(10H)-a n -
th r a cen on e (8) was obtained from the reaction above, along
with 7, as a yellow powder: 15% yield; mp 190 °C; FTIR 1748,
1,8-Dih yd r oxy-10-b en zoyl-9(10H )-a n t h r a cen on e (16).
To a solution of 15 (0.20 g, 0.39 mmol) in 99% ethanol (20 mL)
was added dropwise a solution of 9% aqueous NaOH (5 mL).
The mixture was stirred at room temperature until the
reaction was complete (TLC control). It was then poured into
water (100 mL) and 37% HCl (15 mL) and extracted with CH2-
Cl2 (2 × 50 mL). The combined organic phase was washed
with water (3 × 50 mL), dried over Na2SO4, and evaporated.
Purification by column chromatography afforded yellow
1
1638 cm-1; H NMR (90 MHz, CDCl3) δ 12.53 (s, 1 H), 12.42
(s, 1 H), 8.52 (s, 1 H), 8.30-6.92 (m, 11 H). Anal. Calcd for
C22H14O5: C, 73.74; H, 3.94. Found: C, 73.61; H, 4.10.
1,8-Dih yd r oxy-10-(h yd r oxym eth ylen e)-9(10H)-a n th r a -
cen on e (9). A suspension of 7 (0.3 g, 1.07 mmol) in HOAc
(10 mL), 37% HCl (5 mL), and water (15 mL) was stirred at
room temperature under N2, until the reaction was complete
(TLC control). Water (20 mL) was added, and the mixture
was filtered by suction, washed with water (50 mL), and dried.
Recrystallization from CH2Cl2-methanol (9 + 1) afforded an
orange powder: 64% yield; mp 173 °C dec; 1H NMR (90 MHz,
DMSO-d6) δ 12.82 (s, 2 H), 8.47 (s, 1 H), 7.95-6.73 (m, 6 H),
the enolic OH-signal was absent; MS m/ z ) 254 (28, M+).
Anal. Calcd for C15H10O4: C, 70.86; H, 3.96. Found: C, 70.43;
H, 4.33.
needles: 53% yield; mp 230 °C; FTIR 1681, 1615 cm-1 1H
;
NMR (250 MHz, CDCl3) δ 12.32 (s, 2 H), 7.86-6.79 (m, 11 H),
6.05 (s, 1 H). Anal. Calcd for C21H14O4: C, 76.36; H, 4.27.
Found: C, 76.28; H, 4.27.
1,8-Dia cet oxy-10-[1-[(2-a cet oxyben zoyl)oxy]-1-(2-a ce-
toxyp h en yl)m eth ylen e]-9(10H)-a n th r a cen on e (17) was
prepared from 1426 (0.50 g, 1.15 mmol) and acetylsalicylic acid
chloride (1.19 g, 6 mmol) as described for 15 and afforded a
pale yellow powder: 64% yield; mp 125 °C; FTIR 1769, 1671
10-Ben zoyl-1,8-d im eth oxy-9-h yd r oxya n th r a cen e (13).
A suspension of anhydrous AlCl3 (0.8 g, 6 mmol) in 1,2-
dichloroethane (20 mL) was cooled to 0 °C. Benzoyl chloride
(1.21 g, 8.60 mmol) was added, and the solution was stirred
for 20 min. To this mixture was added a solution of 122 (0.31
g, 1.20 mmol) dropwise at 0 °C under N2, and the mixture was
stirred at 0-5 °C for 3 h. Then it was poured into ice-water
(300 g) and 37% HCl (10 mL), and the mixture was thoroughly
shaken and then extracted with CH2Cl2 (3 × 50 mL). The
combined organic phase was washed with water (3 × 100 mL),
dried over Na2SO4, and evaporated. Purification by column
chromatography (ether) afforded a yellow powder: 64% yield;
1
cm-1; H NMR (90 MHz, CDCl3) δ 7.83-7.03 (m, 14 H), 2.23
(s, 3 H), 2.10 (s, 3 H), 1.77 (s, 6 H). Anal. Calcd for
C36H26O11: C, 68.14; H, 4.13. Found: C, 68.28; H, 4.30.
1,8-Dih yd r oxy-10-(2-h yd r oxyben zoyl)-9(10H)-a n t h r a -
cen on e (18) was prepared from 17 (0.12 g, 0.19 mmol) as
described for 16 and afforded yellow crystals: 59% yield; mp
1
210 °C; FTIR 1688, 1636 cm-1; H NMR (90 MHz, CDCl3) δ
12.57 (s, 1 H), 11.90 (s, 1 H), 10.40 (s, 1 H), 7.68-6.77 (m, 10
H), 6.27 (s, 1 H). Anal. Calcd for C21H14O5: C, 72.83; H, 4.07.
Found: C, 72.56; H, 3.99.
mp 175 °C dec; FTIR 3315, 1667 cm-1 1H NMR (90 MHz,
;
CDCl3) δ 11.32 (s, 1 H), 7.90-6.60 (m, 11 H), 4.10 (s, 6 H).
Anal. Calcd for C23H18O4: C, 77.08; H, 5.06. Found: C, 76.81;
H, 5.01.
Eth er Clea va ge of 13. A solution of 13 (0.20 g, 0.56 mmol)
in dry CH2Cl2 (10 mL) was added dropwise to a solution of
BBr3 (0.70 g, 2.80 mmol) in CH2Cl2 (25 mL) at -78 °C under
Ack n ow led gm en t. We thank Dr. J . D. Berset for
providing a sample of the putative 10-acetylsalicyl-
anthralin.
J O952037L
(26) Hofer, P.; Ott, R. Pharm. Acta Helv. 1974, 49, 35.