Potent antipsoriatic agents: A facile preparation of acylated derivatives from dithranol in a mild basic reaction

Article abstract of DOI:10.1002/jccs.200400018

Treatment of dithranol 1 with various equivalents of acetyl chloride and Et₃N in THF at room temperature afforded the corresponding acylated derivatives, such as 1-acetyloxy- and 1,8-diacetyloxy-9(10H)-anthracenones, 6a, and 6b, as well as 1,8,9-triacetyloxyanthracene 7a, and 1,8,9-triacetyloxy-10- acetylanthracene 7b. 1,8-Bis(trimethylacetyloxy)-9(10H)-anthracenone 6c was also obtained in high yield by using pivaloyl chloride during the mild acylation.

Full text of DOI:10.1002/jccs.200400018

Journal of the Chinese Chemical Society, 2004, 51, 115-118
115
Potent Antipsoriatic Agents: A Facile Preparation of Acylated Derivatives
from Dithranol in a Mild Basic Reaction
David Woei-Ming Liang* (
Department of Applied Chemistry, Providence University, Taichung, 43301, Taiwan, R.O.C.
) and Chun-Jian Du (
)
Treatment of dithranol 1 with various equivalents of acetyl chloride and Et3N in THF at room temperature
afforded the corresponding acylated derivatives, such as 1-acetyloxy- and 1,8-diacetyloxy-9(10H)-anthra-
cenones, 6a, and 6b, as well as 1,8,9-triacetyloxyanthracene 7a, and 1,8,9-triacetyloxy-10-acetylanthracene
7b. 1,8-Bis(trimethylacetyloxy)-9(10H)-anthracenone 6c was also obtained in high yield by using pivaloyl
chloride during the mild acylation.
Keywords: Dithranol; Anthralin; Psoriasis; Acylation; 1,8-Dihydroxy-9(10H)-anthracenone.
INTRODUCTION
Dithranol 1 (also called anthralin, IUPAC nomencla-
of the hydrogen atoms at the C10 position present an attrac-
tive alternative. When both hydrogen atoms were replaced,
the new molecule lost not only its irritative and staining prop-
erties, but also the antipsoriatic activity of the parent com-
pound. When only one of the two hydrogen atoms was re-
placed with an acetyl group, the new molecule retained most
of the properties of dithranol.8 Employing alkaline amines in
the prescription can also help to inactivate dithranol by facili-
tating its oxidation and inhibit dithranol-induced inflamma-
tion by up to 96%.9 Thus, syntheses and biological activities
of 10-acyl substituted dithranol derivatives have been inten-
sively studied recently.10 We report herein the mild acylation
method by treatment of dithranol 1 with acetyl chloride
(AcCl) or pivaloyl chloride (PivCl, trimethylacetyl chloride)
in the presence of triethylamine (Et3N) in tetrahydofuran
(THF) at room temperature.
ture: 1,8-dihydroxy-9(10H)-anthracenone) is the most effec-
tive agent for the treatment of psoriasis.1 However, it is lim-
ited by its undesirable side effects such as irritation and stain-
ing of the skin. Dithranol is not quite stable, and it undergoes
spontaneous oxidation enhanced by day-light, ultraviolent
(UV)-light, exposure to air and molecular oxygen, tempera-
ture increases, the presence of trace metals or tar, alkaline so-
lutions, etc. Intermediate products, such as dithranol anions
1a and 1b, dithranol radicals 1c, and oxygen radicals are
thought to be responsible for both the antipsoriatic effect and
dithranol dermatitis,2 whereas the brown staining is due to the
anthraquinone dimers 4 and polymers,1,3 and both danthron
(1,8-dihydroxyanthraquinone) 2 and dithranol dimer 3 are
not active for the treatment of psoriasis, although they have
no inflammatory effect of the skin.4 Fig. 1 illustrates the topi-
cal oxidation process of dithranol. Consequently, efforts are
being made to understand the molecular basis of the proin-
flammatory and staining properties so that dithranol may be
modified structurally to remove these unpleasant effects.
Dithranol exists almost totally in the ketonic form (an-
throne) in the inert hydrocarbon solvents. In alkaline solu-
tions such as triethylamine and pyridine, it changes to its tau-
tomeric enolic form (anthranol).5 One of the first derivatives
of dithranol was triacetyloxyanthracene (dithranol triacetate)
7a.6 The relative absence of inflammatory reactions and
staining of the skin during the treatment with triacetyloxy-
anthracene was unfortunately accompanied by a slower re-
sponse and a lower antipsoriatic effect in comparison to di-
thranol.7 The analogues of dithranol with partial substitution
RESULTS AND DISCUSSION
Our initial attempts to repeat the O-acetylation of 1, ac-
cording to the literature procedures demonstrated by van
Duuren et al.,11 either by using AcCl (1.2 equiv), pyridine
(1.3 equiv.) in benzene at reflux for 20 h or by using acetic
anhyhride (Ac2O) at reflux afforded the corresponding 10-
acetyl-1,8-dihydroxy-9(10H)-anthracenone 5 and 1,8-di-
acetoxy-9(10H)-anthracenone 6a, respectively. However, al-
though both reactions always gave the reaction mixtures,
they not only contained the various acetyl derivatives includ-
ing the corresponding desired products 6a and 6b, but also
many side-products such as 1,8-dihydroxyanthraquinone 2
and dithranol dimer 3. No desired corresponding 10-acetyl

116 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Liang and Du
derivative 5 was observed; instead, 1,8,9-triacetyloxyanthra-
cene 7a and 10-acetyl-1,8,9-triacetyloxyanthracene 7b were
obtained mainly in low yields. Formation of side-products 2
and 3 may result from the vigorous reaction conditions, i.e. at
reflux for a long time. Thus, a mild acylation method should
be employed for the preparation of acylated dithranol ana-
logues.
equiv.) being used for the acetylation of 1 after 2 h, 1,8,9-
triacetyloxyanthracene 7a and 10-acetylanthracenone triace-
tate 8b were obtained in 84% combined yields, as well as a
trace amounts of 1-acetyloxyanthraquinone 9 (in entry 5). It
is worth noting that the formation of 7b, via Fredel-Craft
acylation in the absence of Lewis acid as catalyst, might be
clarified by that the greater reactivity of 7a is enhanced by
three activated acetyloxy groups located on 1-, 8-, and 9-
positions of the anthracene molecule. All reactions took place
at room temperature without heating and at an atmosphere
pressure of N2 to avoid the formation of side-products, such
as danthron 2 and dithranol dimer 3. It should be noted that
the reaction conditions must be controlled to be basic, i.e.
Et3N being used should be 2.0 equiv. to AcCl, whereas in an
acidic condition the reaction was running very slowly.
Treatment of 1 with AcCl and Et3N in THF at room tem-
perature afforded the corresponding 1-acetyloxyanthrace-
none 6a, 1,8-diacetyloxyanthracenone 6b, 1,8,9-triacetyl-
oxyanthracene 7a, and 10-acetylanthracene triacetate 7b, ac-
companied with a trace of 1-acetyloxydanthron 8 as shown in
Fig. 2 and Table 1. Table 1 illustrates that isolated yields of
the corresponding acetylation products were dependent upon
the equivalents of AcCl and Et3N being employed in the reac-
tions and a period of the reaction time (from entry 2 to entry
4). While 1.0 equiv. of AcCl and 2.0 equiv. of Et3N being used
for the acetylation of 1 only mono-acetylated 6a and di-
acetylated 6b were obtained in 88% combined yields, in
which the former is predominate and the latter is minor (in en-
try 1); whereas excess of AcCl (6.0 equiv.) and Et3N (7.2
Bulky acylating agents such as benzoyl chloride and
p-hydroxybenzoyl chloride were also employed to the acyla-
tion of dithranol, thus the corresponding 1,8-dibenzoyloxy-
9-anthrone and 10-benzoyl-1,8,9-tribenzoyloxyanthracene
were obtained in the high yields reported by Müller et al.10 In
our laboratories pivaloyl chloride was also employed in this
H
H
H
H
OH
O
OH
O
O
O
O
O
O
Base
H
1b
1
1a
Dithranol
-e-
Air,
Light
H
H
O
O
O
H 1c
O2
OH
O
OH
OH
O
OH
OH
O
OH
O2
H
H
O
2
Danthron
OH
O
OH
OH
O
OH
3
4
Dithranol "Dimer"
Anthraquinone "Dimer"
Fig. 1. Autooxidation process of dithranol.

A Facile Preparation of Acylated Dithranols
Table 1. Acetylation of Dithranola
J. Chin. Chem. Soc., Vol. 51, No. 1, 2004 117
acylated derivatives obtained starting from dithranol were
further examined for the clinically therapeutic treatment of
psoriasis.
Entry AcCl
Et3N Reaction
Isolated Yields (%)
(equiv.) (equiv.) Time
6a 6b 7a 7b
8
1
2
3
4
5
1.0
3.0
4.0
4.0
6.0
2.0
6.0
8.0
20 min 76 12
20 min 52 20 15 12
60 min 18 32 30 22 trace
-
-
-
-
EXPERIMENTAL SECTION
8.0 120 min
12.0 120 min
-
-
26 36 36 trace
12 72 trace
1H NMR spectroscopic data for compounds, 6a, 6b, 6c,
7a, 7b, and 8, obtained from the acylation as well as starting
material 1, side-products 2 and 3 are listed in Table 2. HRMS
and IR spectroscopic data for compounds 6a, 6b, 6c, 7a, and
7b are listed in Table 3. 1H NMR spectra were recorded with a
Bruker AC-250 spectrometer (250 MHz), and were refer-
enced to chloroform (d 7.26 ppm) or tetramethylsilane (d
0.00 ppm). Perkin-Elmer Model 883 or JASCO spectrometer
was used for IR spectra. High resolution mass values were
obtained on a JEOL JMS-SX/SX 102A mass spectrometer at
the Department of Chemistry, National Chung-Hsing Univer-
sity. For thin-layer chromatography (TLC) analysis, Merck
precoated TLC plates (Kieselgel 60 F254, 0.2 mm) were used.
Column chromatography was performed by using Merck
Kieselgel 60 (70-230 mesh) as the stationary phase.
-
a All reactions were carried out at room temperature in about 0.1
M of dry THF.
mild acylation method described above, by treatment of 1
with 3.0 equiv. of pivaloyl chloride and 3.6 equiv. of Et3N,
1,8-bis(trimethylacetyloxy)anthracenone 6c was obtained
exclusively in 85% yield, even though excess amounts of
pivaloyl chloride and Et3N were applied, no expected 10-
acylated derivatives were observed. The outcome of this re-
action implied that pivaloyloxyl groups are much more bulky
rather than acetyloxyl and benzoyloxyl groups resulting in
the steric congestion located on the 1-, 8-, and 9-positions of
anthracene molecule, hence, the expected 1,8,9-tripivaloyl-
oxyanthracene and 10-pivaloylanthracene derivatives were
not easily obtained by this mild acylation method.
General Procedure for the Acylation of Dithranol 1
To a solution of 1 (1 mmol) in 10 mL of dry THF was
added Et3N followed by AcCl or PivCl at room temperature
under N2. The reaction mixture was monitored by TLC until
CONCLUSION
In conclusion, the corresponding acetylated dithranol
analogues, 6a, 6b, 7a, and 7b, were easily prepared in a mild
basic reaction condition, in which the corresponding prod-
ucts were obtained according to how many equivalents of
AcCl and Et3N were employed and a period of reaction time.
1,8-Bis(trimethylacetyloxy)anthracenone 6c was also ob-
tained in high yield by using this mild acylation method. All
Table 2. 1H NMR (250 MHz, CDCl3) Spectroscopic Data
Compd
d (ppm)
1
4.35 (s, 2H), 6.90 (d, J = 8 Hz, 4H), 7.49 (t, J = 8 Hz,
2H), 12.30 (s, 2H)
2
7.32 (d, J = 8 Hz, 2H), 7.71 (t, J = 8 Hz, 2H), 7.85 (d, J
= 8 Hz, 2H), 12.10 (s, 2H)
OR2
O
OR1
OR1 OR1 OR1
3
4.60 (s, 2H), 6.38 (d, J = 8 Hz, 4H), 6.91 (d, J = 8 Hz,
4H), 7.39 (t, J = 8 Hz, 4H), 11.70 (s, 4H)
2.46 (s, 3H), 4.35 (s, 2H), 6.84-6.89 (m, 2H), 7.05 (d, J =
8 Hz, 1H), 7.32 (d, J = 8 Hz, 1H), 7.43 (t, J = 8 Hz, 1H),
7.59 (t, J = 8 Hz, 1H), 12.80 (s, 1H)
6a
R2
7a R1=Ac, R2=H
6a R1=Ac, R2=H
6b R1=R2=Ac
6c R1=R2=Piv
7b R1=R2=Ac
6b
6c
7a
7b
8
2.48 (s, 6H), 4.32 (s, 2H), 6.96 (d, J = 8 Hz, 4H), 7.28 (t,
J = 8 Hz, 2H), 7.54 (d, J = 8 Hz, 2H)
1.45 (s, 18H), 4.30 (s, 2H), 6.95 (d, J = 8 Hz, 4H), 7.28
(t, J = 8 Hz, 2H), 7.52 (d, J = 8 Hz, 2H)
2.43 (s, 9H), 7.14 (d, J = 8 Hz, 2H), 7.44 (t, J = 8 Hz,
2H), 7.90 (d, J = 8 Hz, 2H), 8.43 (s, 1H)
2.42 (s, 9H), 2.81 (s, 3H), 7.17 (d, J = 8 Hz, 2H), 7.51 (t,
J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H)
OH
O
OAc
OH
O
OH
O
8
Ac
5
2.45 (s, 6H), 7.41 (d, J = 8 Hz, 2H), 7.76 (t, J = 8 Hz,
2H), 8.22 (d, J = 8 Hz, 2H)
Fig. 2. Acylated derivatives from dithranol 1.

118 J. Chin. Chem. Soc., Vol. 51, No. 1, 2004
Liang and Du
Table 3. HRMS and IR Spectroscopic Data
Compd Molecular
Formula
HRMS
Found
IR (KBr)
cm-1 (functional group, rel. intensity)
Calcd
6a
C16H12O4 268.0736 268.0730 3450 (OH, vs), 1740 (C=O of OAc, vs), 1610
(OH-O=C, vs)
6b
6c
7a
7b
C18H14O5 310.0841 310.0848 1760 (C=O of OAc, vs), 1660 (C=O, s)
C24H26O5 394.1781 394.1788 1750 (C=O of PivO, vs), 1650 (C=O, s)
C20H16O6 352.0947 352.0942 1750 (C=O of OAc, vs)
C22H18O7 394.1052 394.1056 1750 (C=O of OAc, vs), 1650 (C=O of Ac, s)
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1960, 293, 918.
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layers were washed with 10% aq. NaHCO3 solution, water,
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chromatography on silica gel eluting with EtOAc/hexane to
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ACKNOWLEDGMENT
The authors are grateful to Dr. W.-C. Wang (M.D.) for
the supply of dithranol, and Taichung Veteran’s Hospital for
the financial support.
Received February 12, 2003.
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