Acetylation of 2-(1-piperazinyl)- and 2-morpholino-1,4-dihydroxyanthraquinones

Article abstract of DOI:10.1023/A:1022520925284

Successive acetylation of 2-(1-pipepazinyl)- and 2-morpholino-1,4-dihydroxyanthraquinones with acetic anhydride was accomplished.

Full text of DOI:10.1023/A:1022520925284

Russian Journal of Organic Chemistry, Vol. 38, No. 10, 2002, pp. 1519 1524. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 10, 2002,
pp. 1572 1576.
Original Russian Text Copyright
2002 by Loskutov, Nekhoroshev.
Acetylation of 2-(1-Piperazinyl)-
and 2-Morpholino-1,4-dihydroxyanthraquinones
V. A. Loskutov and S. A. Nekhoroshev
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: vsh@nioch.nsc.ru
Received February 8, 2002
Abstract Successive acetylation of 2-(1-pipepazinyl)- and 2-morpholino-1,4-dihydroxyanthraquinones with
acetic anhydride was accomplished.
Hydroxyanthraquinone derivatives are pharmaco-
logically active substances [1 6]. In particular, acyl-
(or alkyl)oxyanthraquinones exhibit antitumor [1, 2],
immunotropic [3], and antiviral [4] activity.
We have found that acetylation of compounds Ia Ig
under milder conditions gives not only exhaustive but
also partial acetylation products. Treatment of 1,4-di-
hydroxy-2-(1-piperazinyl)anthraquinone with acetic
anhydride at 20 25 C resulted in acetylation of only
the NH group, and the corresponding 2-(4-acetyl-1-
piperazinyl) derivative II was obtained in 55% yield
(Scheme 1).
It is known that esterification of -hydroxyanthra-
quinones requires the presence of an acid or base, for
the -hydroxy group in the substrate is involved in
intramolecular hydrogen bond with the carbonyl
oxygen atom [6]. Correspondingly, treatment of com-
pound Ia with acetic anhydride at 20 25 C in the
presence of a catalytic amount of sulfuric acid leads
to acetylation not only of the NH group but also of
the hydroxy groups. Here, the 4-hydroxy group, which
is more distant from the 2-substituent, is acetylated
first. The isolation of individual compounds from
mixtures of N,O-diacetyl and N,O,O -triacetyl deriva-
tives III and IV was complicated by the sensitivity of
the O-acetyl derivatives to hydrolysis, as well as by
more or less considerable tarring (depending on the
reaction time). The best conditions for the preparation
of product III were treatment of N-acetyl derivative
X = NH (a), NMe (b), NEt (c), NPh (d), NCHPh2 (e),
O (f), S (g).
With the goal of searching for new biologically
active compounds in the hydroxyanthraquinone series
we have studied acetylation of 2-amino-substituted
1,4-dihydroxyanthraquinones (quinizarins) Ia Ig
having piperazinyl and morpholino groups. It is
known that the presence of these groups enhances
biological activity [7, 8]. Fokin et al. [9] described the
reaction of 1,4-dihydroxy-2-piperidinoanthraquinone
with acetic anhydride in pyridine at 100 C, which
resulted in acetylation of the two hydroxy groups.
Scheme 1.
1070-4280/02/3810-1519$27.00 2002 MAIK Nauka/Interperiodica

1520
LOSKUTOV, NEKHOROSHEV
Scheme 2.
V, VI, X = NMe (b), NEt (c), NPh (d), NCHPh2 (e), O (f), S (g).
II with acetic anhydride in the presence of H2SO4 for
a short time; and the best results in the preparation of
compound IV were obtained by acetylation of anthra-
quinone Ia in pyridine on heating.
(by 4 nm), while the corresponding shifts for N,O-di-
acetyl and N,O,O -triacetyl derivatives III and IV
are 43 and 106 nm, respectively.
The structure of the products was established on the
basis of their analytical and spectral data (Tables 1, 2).
Substituted anthraquinones Ib Ig reacted with
acetic anhydride at 20 25 C, following a similar
scheme. Under conditions of acid catalysis, mono-O-
acetyl derivatives Vd Vg were obtained in a good
yield (50 70%). However, the acetylation of more
basic N-alkylpipepazinyl compounds was less smooth.
Monoacetate Vb was isolated from the reaction mix-
ture in a fairly poor yield (26%), while compound Vc
was obtained with an acceptable yield only when the
reaction was carried out under conditions of base
catalysis (in pyridine). Analogous conditions (heating
in pyridine) were applied to synthesize diacetates VId
and VIf from aminoanthraquinones Id and If. Di-
acetates VIe and VIg are less sensitive to hydrolysis,
and they can be obtained by acetylation in the pres-
ence of H2SO4 of monoacetate Ve and thiomorpho-
linoanthraquinone Ig, respectively. It should be noted
that we failed to isolate analytically pure O,O -di-
acetates derived from N-alkylpipepazinyl derivatives
Ib and Ic, for these products turned out to be insuf-
ficiently stable.
1
In the H NMR spectra of dihydroxyanthraquinones
I and II, signals from the hydroxy protons appear as
singlets at 14.3 (1-OH) and 13.5 ppm (4-OH). The
substituent in position 2 exerts a stronger deshielding
effect on the proton of the neighboring hydroxy group
in position 1, as compared to the more distant
4-hydroxy group [10]. In keeping with the above
stated, the spectra of 4-acetoxy derivatives III and
V contain only one downfield signal at
14.3 ppm,
which belongs to the hydroxy proton in position 1.
The spectra of 1,4-diacetates IV and VI lack signals
in that spectral region. The IR spectra of compounds
I VI are characterized by the presence of carbonyl
absorption bands at 1650 1670 (C O, quinone),
1614 1640 (C O, quinone, involved in hydrogen
bond with the hydroxy group), 1650 (N-acetyl
group), and 1750 1770 cm 1 (O-acetyl group).
The main fragmentation pathway of acetylated
compounds II IV under electron impact is elimina-
tion of the acetyl groups and subsequent cleavage
of the heteroring, leading to the quinizarin molecular
ion with m/z 240). For example, triacetyl derivative
IV successively loses O-acetyl groups with expulsion
of two ketene molecules (m/z 42) and formation of
rearranged ions F1 and F2, which is consistent with
the lower stability of acetates. Ion F2 loses N-acetyl
group (m/z 43) to give ion F3. Cleavage of the hetero-
ring involves successive elimination of CH2N and
Compounds I VI are crystalline substances which
are soluble in most organic solvents. The color of
2-amino derivatives is deeper than that of quinizarin.
Esterification of the hydroxy groups is accompanied
by a considerable blue shift of the long-wave absorp-
tion maximum. In going from piperazinyl derivative
Ia to N-acetyl derivatives II, the position of the long-
wave absorption maximum changes insignificantly
Scheme 3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

ACETYLATION OF 2-(1-PIPERAZINYL)- . . .
1521
Table 1. Yields, melting points, elemental analyses, and molecular weights of compounds I VI
Found, %
H
Calculated, %
M
Comp. Yield,
mp,
(solvent)
C
Formula
no.
%
C
N
C
H
N
found
calcd.
Ia
50
27
29
40
50
66
55
61
36
26
59
71
46
69
66
59
58
62
29
206 208
(EtOH)
219 222
66.76 4.99 8.20 C18H16N2O4
67.13 5.47 7.92 C19H18N2O4
7.93 C20H20N2O4
66.66 4.93 8.64 324.1107 324.1110
67.45 5.32 8.28
Ib
(CHCl3 MeOH)
191 192.5
(CHCl3 MeOH)
240 241.5
(CHCl3)
216 218
(C6H6 EtOH)
259 261
(CHCl3 MeOH)
226 229
Ic
7.95
Id
72.30 4.95 6.95 C24H20N2O4
76.83 5.53 5.71 C31H26N2O4
4.26 C18H15NO4Sa
72.00 5.00 7.00 400.1415 400.1423
75.92 5.31 5.71
Ie
Ig
4.10
II
65.47 4.95 7.77 C20H18N2O5
64.00 4.88 6.95 C22H20N2O6
64.22 4.88 5.84 C24H22N2O7
66.70 5.11 7.67 C21H20N2O5
66.40 5.61 6.90 C22H22N2O5
70.15 5.04 6.10 C26H22N2O5
73.69 5.74 4.83 C33H28N2O5
65.26 4.51 3.55 C20H17NO6
62.47 4.35 3.21 C20H17NO5S
69.11 4.82 5.59 C28H24N2O6
73.55 5.40 4.79 C35H30N2O6
64.21 4.74 3.35 C22H19NO7
65.57 4.91 7.65 366.1221 366.1216
64.70 4.90 6.86 408.1316 408.1321
64.00 4.89 6.22 450.1414 450.1427
66.31 5.26 7.36
(CHCl3 MeOH)
176 179
III
IV
Vb
Vc
Vd
Ve
Vf
(MeOH)
166 169
(CH2Cl2 Et2O)
196 199
(CH2Cl2 Et2O)
188 190
(MeOH)
207 210
(CH2Cl2 MeOH)
219 222
(CH2Cl2 MeOH)
203 208
(C6H6)
206 208
(CHCl3 MeOH)
175 177
(CH2Cl2 MeOH)
198 202
(CH2Cl2 MeOH)
214 217
(CH2Cl2 MeOH)
186 189
67.00 5.58 7.10 394.1538 394.1529
70.58 4.97 6.33
74.44 5.26 5.26 532.1999 532.1998
65.39 4.63 3.81 367.1051 367.1056
62.66 4.44 3.65
Vg
VId
VIe
VIf
VIg
69.42 4.96 5.78
73.17 5.23 4.88
64.55 4.64 3.42
61.56 4.51 2.88 C22H19NO6Sb 62.12 4.47 3.29 425.0891 425.0933
(CH2Cl2 MeOH)
a
Found, %: S 9.50. Calculated, %: S 9.38.
Found, %: S 6.96. Calculated, %: S 7.53.
b
CH fragments (which is typical of saturated nitrogen-
containing heterocycles). This pathway is confirmed
by the presence of peaks from ions F4 F7 in the high-
resolution mass spectrum (Scheme 3). The fragmenta-
tion of monoacetates Vc, Ve, and Vf and diacetate
VIg follows a similar pattern. Previously unknown
2-amino-1,4-dihydroxyanthraquinones Ia Ie and Ig
were synthesized by known method, amination of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

1522
LOSKUTOV, NEKHOROSHEV
Table 2. IR and 1H NMR spectra of compounds I VI
1
IR spectrum, , cm
Comp.
no.
1H NMR spectrum, , ppm
C O
C C
1584
Ia
Ib
Ic
3.05 m, 3.40 m (8H, 4CH2), 6.53 s (1H, 3-H), 7.75 m (2H, 6-H, 7-H), 8.28 m 1640, 1617
(2H, 5-H, 8-H)a
2.35 s (3H, CH3), 2.60 m, 3.43 m (8H, 4CH2), 6.54 s (1H, 3-H), 7.75 m (2H, 1635 sh, 1614
6-H, 7-H), 8.28 m (2H, 5-H, 8-H), 13.52 s (1H, 4-OH), 14.32 s (1H, 1-OH)
1582
1586
1.12 t, 2.49 q (5H, CH3CH2), 2.65 m, 3.45 m (8H, 4CH2), 6.55 s (1H, 3-H), 1636, 1614
7.75 m (2H, 6-H, 7-H), 8.29 (2H, 5-H, 8-H), 13.54 s (1H, 4-OH), 14.34 s
(1H, 1-OH)
Id
Ie
3.39 m, 3.56 m (8H, 4CH2), 6.63 s (1H, 3-H), 6.97 m, 7.29 m (5H, Harom), 1634, 1614
7.78 m (2H, 6-H, 7-H), 8.32 m (2H, 5-H, 8-H), 13.55 s (1H, 4-OH), 14.35 s
(1H, 1-OH)
1583
1585
2.62 m, 3.43 m (8H, 4CH2), 4.29 s (1H, CH), 6.53 s (1H, 3-H), 7.15 m, 1629 sh, 1616
7.44 m (10H, Harom), 7.75 m (2H, 6-H, 7-H), 8.30 m (2H, 5-H, 8-H),
13.58 s (1H, 4-OH), 14.32 s (1H, 1-OH)
If
3.39 m, 3.90 m (8H, 4CH2), 6.57 s (1H, 3-H), 7.78 m (2H, 6-H, 7-H), 8.31 m 1633 sh, 1618
(2H, 5-H, 8-H), 13.50 s (1H, 4-OH), 14.29 s (1H, 1-OH)
1587
1583
1584
Ig
II
2.82 m, 3.68 m (8H, 4CH2), 6.57 s (1H, 3-H), 7.77 m (2H, 6-H, 7-H), 8.32 m 1626 sh, 1615
(2H, 5-H, 8-H), 13.50 s (1H, 4-OH), 14.26 s (1H, 1-OH)
2.14 s (3H, COCH3), 3.33 m, 3.40 m, 3.66 m, 3.80 m (8H, 4CH2), 6.51 s (1H, 1652, 1634, 1615
3-H), 7.76 m (2H, 6-H, 7-H), 8.26 m (2H, 5-H, 8-H), 13.40 s (1H, 4-OH),
14.20 s (1H, 1-OH)
III
2.14 s, 2.45 s, (6H, 2COCH3), 3.28 m, 3.37 m, 3.66 m, 3.82 m (8H, 4CH2), 1768, 1656, 1629
6.70 s (1H, 3-H), 7.75 m (2H, 6-H, 7-H), 8.25 m (2H, 5-H, 8-H), 14.23 s
(1H, 1-OH)
1591
IV
2.13 s, 2.48 s (9H, 3COCH3), 3.24 br.m, 3.60 m, 3.75 m (8H, 4CH2), 6.90 1775, 1673, 1650
(1H, 3-H), 7.70 m (2H, 6-H, 7-H), 8.12 m (2H, 5-H, 8-H)
1590
1592
Vb
2.35 s (3H, CH3), 2.44 s (3H, COCH3), 2.61 m, 3.38 m (8H, 4CH2), 6.69 s 1760, 1660, 1624
(1H, 3-H), 7.73 m (2H, 6-H, 7-H), 8.22 m (2H, 5-H, 8-H), 14.27 s (1H,
1-OH)
Vc
Vd
Ve
1.12 t, 2.49 q (5H, CH3CH2), 2.45 s (3H, COCH3), 2.64 m, 3.42 m (8H, 1761, 1660, 1623
4CH2), 6,69 s (3-H), 7.74 m (2H, 6-H, 7-H), 8.24 m (2H, 5-H, 8-H),
14.28 s (1H, 1-OH)
1585
1592
1585
2.46 s (3H, COCH3), 3.38 m, 3.53 m (8H, 4CH2), 6.75 s (1H, 3-H), 6.95 m, 1759, 1660, 1625
7.28 m (5H, Harom), 7.75 m (2H, 6-H, 7-H), 8.25 m (2H, 5-H, 8-H), 14.28 s
(1H, 1-OH)
2.45 s (3H, COCH3), 2.60 m, 3.39 m (8H, 4CH2), 4.30 s (1H, CH), 7.24 m, 1769, 1656, 1640
7.44 m (10H, Harom), 7.74 m (2H, 6-H, 7-H), 8.22 m (2H, 5-H, 8-H),
14.24 s (1H, 1-OH)
Vf
2.45 s (3H, COCH3), 3.34 m, 3.89 m (8H, 4CH2), 6.69 s (1H, 3-H), 7.73 m 1757, 1656, 1623
(2H, 6-H, 7-H), 8.23 m (2H, 5-H, 8-H), 14.24 s (1H, 1-OH)
1589
1590
1592
Vg
VId
2.46 s (3H, COCH3), 2.83 m, 3.59 m (8H, 4CH2), 6.71 s (1H, 3-H), 7.74 m 1755, 1656, 1627
(2H, 6-H, 7-H), 8.24 m (2H, 5-H, 8-H), 14.20 s (1H, 1-OH)
2.46 s, 2.48 s (6H, 2COCH3), 3.32 m, 3.45 m (8H, 4CH2), 6.94 m, 7.24 m 1774, 1671
(6H, Harom, 3-H), 7.69 m (2H, 6-H, 7-H), 8.13 m (2H, 5-H, 8-H)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

ACETYLATION OF 2-(1-PIPERAZINYL)- . . .
1H NMR spectrum, , ppm
1523
Table 2. (Contd.)
1
IR spectrum, , cm
C O
Comp.
no.
C C
1581
VIe
2.41 s, 2.47 s (6H, 2COCH3), 2.53 m, 3.25 m (8H, 4CH2), 4.26 s (1H, CH), 1772, 1674, 1659
6.87 s (1H, 3-H), 7.23 m, 7.36 m (10H, Harom), 7.68 m (2H, 6-H, 7-H),
8.11 m (2H, 5-H, 8-H)
VIf
2.46 s, 2.47 s (6H, 2COCH3), 3.21 br.m, 3.82 m (8H, 4CH2), 6.90 s (1H, 3-H), 1770, 1672
7.69 m (2H, 6-H, 7-H), 8.12 m (2H, 5-H, 8-H)
1590
1591
VIg
2.47 s, 2.48 s (6H, 2COCH3), 2.76 m, 3.44 m (8H, 4CH2), 6.91 s (1H, 3-H), 1777, 1670, 1651
7.70 m (2H, 6-H, 7-H), 8.10 m (2H, 5-H, 8-H)
a
Signals from the OH and NH protons are not observed in the spectrum due to exchange.
quinizarin in pyridine at 50 60 C in the presence of
boric acid [6, 9] (Scheme 4).
2-(4-Acetyl-1-piperazinyl)-1,4-dihydroxyanthra-
quinone (II). A mixture of 0.32 g of compound Ia
and 5 ml of acetic anhydride was kept for 96 h at
20 25 C. The red precipitate was filtered off, washed
with diethyl ether, and recrystallized from chloro-
form methanol. Yield 0.2 g. Electron absorption spec-
trum, max, nm ( ): 268 (27710), 313 (8200), 506
(12135).
Scheme 4.
4-Acetoxy-2-(4-acetyl-1-piperazinyl)-1-hydroxy-
anthraquinone (III). A mixture of 0.12 g of com-
pound II, 5 ml of acetic anhydride, and 0.03 ml of
concentrated sulfuric acid was stirred for 3 h at 20
25 C. Ice was then added, and the red precipitate was
filtered off and recrystallized from methanol. Yield
0.08 g. Electron absorption spectrum, max, nm ( ):
260 (29114), 309 (8862), 467 (6724).
EXPERIMENTAL
The IR spectra were recorded on a Vector 22 spec-
trometer in KBr. The electron absorption spectra were
measured on a Hewlett Packard 8453 instrument in
1
chloroform. The H NMR spectra were obtained on
Acetates Vb, Vd Vg, and VIg were synthesized
in a similar way from anthraquinones Ib and Id Ig,
respectively, and diacetate VIe, from monoacetoxy
derivative Ve. Diacetate VIg was isolated from the
mother liquor by column chromatography on silica gel
using benzene as eluent.
1,4-Diacetoxy-2-(4-acetyl-1-piperazinyl)anthra-
quinone (IV). a. A mixture of 0.48 g of compound
Ia, 8 ml of acetic anhydride, and 0.06 ml of concen-
trated sulfuric acid was kept for 25 days at 20 25 C.
The black tar-like precipitate was filtered off and
washed with methanol. The filtrate was poured into
ice water, and the yellow brown precipitate was
separated and recrystallized from methylene chloride
diethyl ether. Yield 0.08 g (12%). Electron absorption
spectrum, max, nm ( ): 250 (24800), 297 (17884),
404 (5492).
a Bruker WP-200SY spectrometer in CDCl3 using the
residual proton signal of the solvent as reference. The
mass spectra were run on a Finnigan MAT-8200 mass
spectrometer; the molecular weights and elemental
compositions were determined from the precise m/z
values. The progress of reactions was monitored,
and the purity of products was checked, by TLC
on Silufol UV-254 plates using chloroform acetone
(10:1) as eluent.
2-(1-Pipepazinyl)-1,4-dihydroxyanthraquinone
(Ia). A mixture of 1.2 g of quinizarin, 0.4 g of boric
acid, and 1.3 g of piperazine in 15 ml of pyridine was
stirred for 3 h at 50 60 C. After cooling, the precip-
itate was filtered off, washed with ethanol, and recrys-
tallized from ethanol. Yield 0.8 g. Electron absorption
spectrum, max, nm ( ): 247 (17852), 271 (22130),
317 (7508), 510 (10880).
Compounds Ib Ig were synthesized in a similar
way. Compound If: yield 40%, mp 249 252 C; pub-
lished data [9]: mp 251 252 C.
b. A mixture of 0.16 g of compound Ia, 1 ml of
pyridine, and 0.5 ml of acetic anhydride was heated
for 2 h at 50 60 C. It was then poured into ice water,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 10 2002

1524
LOSKUTOV, NEKHOROSHEV
and the precipitate was filtered off, recrystallized
from methylene chloride methanol, and washed with
diethyl ether. Yield 0.08 g.
4. Litvinova, L.A., Andronati, S.A., Lempart, G.V.,
Isaev, S.D., Yasinskaya, O.G., and Ivanova, V.V.,
Khim.-Farm. Zh., 1983, vol. 17, no. 2, pp. 19 20.
5. Muller, K., Gen. Pharmacol., 1996, vol. 27, no. 8,
Compounds Vc, VId, and VIf were synthesized in
a similar way from aminoanthraquinones Ic, Id, and
If, respectively.
pp. 1325 1335.
6. Gorelik, M.V., Khimiya antrakhinonov i ikh proiz-
vodnykh (Chemistry of Anthraquinones and Their
Derivatives), Moscow: Khimiya, 1983.
REFERENCES
7. Mokrushina, G.A., Charushin, V.I., and Chupa-
khin, O.N., Khim.-Farm. Zh., 1995, vol. 29, no. 9,
pp. 5 19.
8. Litvinova, L.A., Lyakhov, S.A., Andronati, S.A.,
Zhukova, N.A., Yasinskaya, O.G., Galkin, B.N.,
Filippova, T.O., and Golovenko, N.Ya., Khim.-Farm.
Zh., 1998, vol. 32, no. 12, pp. 14 17.
1. Bogatskii, A.V., Kavetskii, R.E., Litvinova, L.A.,
Lempart, G.V., Andronati, S.A., Balitskii, K.P.,
Umanskii, Yu.A., Veksler, I.G., Yakimenko, L.V.,
and Filippova, T.O., Khim.-Farm. Zh., 1978, vol. 12,
no. 4, pp. 46 50.
2. Jin, G.-Z., Song, G.-Y., Zheng, X.-G., Kim, Y.,
Sok, D.-E., and Ahn, B.-Z., Arch. Pharm. Res., 1998,
vol. 21, no. 2, pp. 198 206.
9. Fokin, E.P., Russkikh, V.V., Russkikh, S.A., and
Mazur, V.G., Zh. Prikl. Khim., 1971, vol. 44, no. 10,
pp. 2271 2276.
3. Litvinova, L.A., Lempart, G.V., Andronati, S.A., and
Filippova, T.O., Khim.-Farm. Zh., 1980, vol. 14,
no. 10, pp. 34 37.
10. Russkikh, S.A., Loskutov, V.A., and Russkikh, V.V.,
Zh. Obshch. Khim., 1974, vol. 44, no. 3, pp. 642 648.
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